Clovibactin and Staphylococcus aureus: a new weapon against resistant strains

dgkh000501 10.3205/dgkh000501 urn:nbn:de:0183-dgkh0005018 Narrative Review Clovibactin and Staphylococcus aureus: a new weapon against resistant strains Clovibactin und Staphylococcus aureus: ein neuer Schutz gegen resistente Stämme Adeiza Adeiza Shuaibu Suleiman SS

Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical sciences, Ahmadu Bello University, Zaria, Kaduna, Nigeria. Department of Clinical pharmacy and Pharmacy Practice, Usmanu Danfodiyo University, Sokoto, Nigeria, Phone: +23 48162208444Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Kaduna, NigeriaDepartment of Clinical Pharmacy and Pharmacy Practice, Usmanu Danfodiyo University, Sokoto, Nigeria

suleykestler2@gmail.com author German Medical Science GMS Publishing House

Düsseldorf

610 clovibactin Staphylococcus aureus antimicrobial resistance Eleftheria terrae Clovibactin Staphylococcus aureus antimikrobielle Resistenz Eleftheria terrae 20241023 engl This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). 2196-5226 19 GMS Hygiene and Infection Control GMS Hyg Infect Control 46 Clovibactin ist ein neues Depsipeptid und hoch wirksam gegen Staphylococcus (S.) aureus, einschließlich Methicillin-resistentem und Vancomycin-resistentem S. aureus ohne erkennbare Resistenz. Clovibactin übertrifft die derzeitigen Antibiotika wie Vancomycin. Wir erörtern hier die Wirksamkeit, den dringenden Bedarf an neuen Antibiotika aufgrund der weltweit zunehmenden Antibiotikaresistenz, den Wirkungsmechanismus und mögliche Vorteile gegenüber den derzeitigen Behandlungen. Außerdem werden die Probleme bei der Herstellung in großem Maßstab und der Stand der Forschung zur Entwicklung wirksamer und weniger toxischer Derivate beleuchtet. Clovibactin is a new depsipeptide and highly efficacious against Staphylococcus (S.) aureus, including methicillin-resistant and vancomycin-resistant S. aureus, with no apparent resistance. Clovibactin o</PlainText></TextGroup>utclasses current antibiotics such as vancomycin. Here, we discuss its efficacy, emphasize the need for new antibiotics owing to growing global antibiotic resistance, highlight its mode of action and possible benefits over current treatments. We also highlight the challenges involved in large-scale manufacturing and the status of continuing research to advance effective and less toxic derivatives.</Pgraph></Abstract> <TextBlock linked="yes" name="Introduction"> <MainHeadline>Introduction</MainHeadline><Pgraph>Antibiotics may be classified based on the part of the cell they affect, also based on whether they cause cell inhibition (bacteriostatic) or death (bactericidal) <TextLink reference="1"></TextLink>. The majority of bactericidal drugs inhibit synthesis of either the cell wall, DNA, RNA, or protein <TextLink reference="1"></TextLink>. Cell death caused by antibiotics is a process that starts with a drug molecule interacting with its target bacteria, followed by biochemical, molecular, and ultrastructural changes in the target <TextLink reference="2"></TextLink>. The ability of antibiotics to kill bacteria usually involves blocking DNA gyrase, which promotes the breakage of double-stranded DNA, stopping DNA synthesi<TextGroup><PlainText>s, and d</PlainText></TextGroup>amaging the cell envelope. Additionally, blocking cell wall formation results in the destruction of cell wall stability <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>. Certain antibiotics interfere with translation, causing protein synthesis errors and increasing cellular energy demand for stress management. This diverts resources from other processes, reducing efficiency and raising energy consumption <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>. In the case of drug resistance, the actions of antibiotics mentioned above, including killing or inhibiting bacteria by targeting the cellular processes, will fail <TextLink reference="5"></TextLink>.</Pgraph><Pgraph>After the golden age of antibiotic discovery (1940s–1960s), the field faced great challenges in the decades that followed, and no new antibiotics were developed <TextLink reference="6"></TextLink>. Antibiotic resistance killed about <TextGroup><PlainText>1,270,000 people world-wide in 2019 and has since c</PlainText></TextGroup>ontributed to four times more deaths as resistance continues to rise globally <TextLink reference="7"></TextLink>. In WHO African regions, bacteria-associated Antimicrobial resistance (AMR) deaths were estimated to be 1.05 million: of these 250,000 were linked directly to AMR in 2019 <TextLink reference="8"></TextLink>. Over 100,000 of these deaths were linked to <Mark2>S. aureus</Mark2> (MRSA was the chief culprit) <TextLink reference="8"></TextLink>. By 2050, AMR could result in over 10 million deaths annually, outstripping cancer as the leading cause of death <TextLink reference="9"></TextLink>.</Pgraph><Pgraph><Mark2>Staphylococcus (S.) aureus</Mark2>, chiefly those strains that are resistant to vancomycin (VRSA) and methicillin (MRS<TextGroup><PlainText>A), i</PlainText></TextGroup>s ranked among the top six most menacing drug-resistant bacteria for which newer antibiotics are needed <TextLink reference="10"></TextLink>. <TextGroup><Mark2>S</Mark2><PlainText>. </PlainText><Mark2>a</Mark2></TextGroup><Mark2>ureus</Mark2> is harmful and causes infections in both soft tissue and skin <TextLink reference="11"></TextLink>. Left unattended, these infections can result in serious conditions such as bacteraemia or septic shock, with significant death rates <TextLink reference="12"></TextLink>. In people aged 15 and older, <Mark2>S. aureus</Mark2> is the leading cause of bacteria-associated deaths globally <TextLink reference="12"></TextLink>. In 2019, around 569,00<TextGroup><PlainText>0 m</PlainText></TextGroup>ortalities were attributed to antibiotic resistant bacteria in the Americas (WHO-regions), with a confidence interval between 406,000 and 771,000 <TextLink reference="13"></TextLink>. Furthermore, 141,000 mortalities were directly triggered by these bacteria, with the spectrum projected to be in the range of 99,900 to 196,000 <TextLink reference="13"></TextLink>.</Pgraph><Pgraph>Today, innovative technologies, e.g., machine learning, quantum computing and next-generation sequencing, are speeding up the identification of bacterial drug resistance and helping us to better understand the genes responsible for them <TextLink reference="14"></TextLink>. Scientists are also working on novel treatments, for instance, antimicrobial peptides, phage therapy, vaccines, treatments that target the host’s own cells, and photodynamic therapy <TextLink reference="10"></TextLink>. But treatment of diseases/infections caused by bacteria still largely consists of antibiotics. Excessive use of these drugs has led to a strong upsurge in drug-resistant strains such as MRSA <TextLink reference="15"></TextLink>. MRSA infections are worse than methicillin susceptible strains , more expensive to treat, and require longer hospital stays <TextLink reference="16"></TextLink>. MRSA causes many HAIs (hospital-acquired infections) and the last resort-antibiotic, vancomycin, is failing with increasing frequency <TextLink reference="17"></TextLink>. The importance of finding new antibiotics cannot be overstated <TextLink reference="18"></TextLink>. In a 2023 breakthrough by Shukla et al., clovibactin was discovered (Figure 1 <ImgLink imgNo="1" imgType="figure"/>). Using the isolation chip or iChip device, it was isolated from an uncultured bacterium <TextLink reference="19"></TextLink>. Markus Weingarth et al. at Utrecht University in the Netherlands have studied clovibactin and found that it outperforms vancomycin as a potent MRSA killer <TextLink reference="19"></TextLink>.</Pgraph><Pgraph>Clovibactin is an antibiotic that kills Gram-positive pathogenic, drug-resistant bacteria <TextLink reference="20"></TextLink>. It was harvested from an uncultured bacterium found in the soil <TextLink reference="19"></TextLink>. No resistance to it has yet been found <TextLink reference="21"></TextLink>. This compound targets the pyrophosphate of the precursors of peptidoglycan (PG) (lipid II, lipid IIIWTA and C55PP), thereby blocki<TextGroup><PlainText>ng t</PlainText></TextGroup>he cell wall synthesis of organisms of interest <TextLink reference="22"></TextLink>. This mode of action was confirmed using atomic force microscopy, nuclear magnetic resonance (solid state) and biochemical tests <TextLink reference="23"></TextLink>. It accounts for lack of resistance by using a rare hydrophobic interphase that wraps tightly around pyrophosphate and avoids variable precursor structural elements <TextLink reference="23"></TextLink>. For some bacterial membranes that have lipid groups with pyrophosphate, this antibiotic achieves specificity and efficiency for effective bacteriocide by forming supramolecular fibril structures <TextLink reference="24"></TextLink>. This technique helps in creation of better drugs with less potential for resistance developing in its target <TextLink reference="24"></TextLink>. </Pgraph><Pgraph>The purpose of this review is to describe clovibactin as a novel antibiotic that is effective against <Mark2>S. aureus</Mark2> and its drug-resistant strains, including MRSA, and emphasize the pressing requirement for innovative treatment options with new antibiotics like clovibactin and its analogues to fight resistance to antibiotics.</Pgraph></TextBlock> <TextBlock linked="yes" name="Discovery of clovibactin from Eleftheria terrae"> <MainHeadline>Discovery of clovibactin from Eleftheria terrae</MainHeadline><Pgraph>The isolation chip or iChip device (Figure 2 <ImgLink imgNo="2" imgType="figure"/>) helps researchers cultivate bacteria that were formerly difficult to grow <TextLink reference="25"></TextLink>. It functions by taking bacterial samples, trapping them in microwells on the chip, and then returning the chip to its natural habitat so that the bacteria can flourish <TextLink reference="25"></TextLink>. This system has brought about a massive rise (30,000%) in microbial growth when compared to traditional methods <TextLink reference="26"></TextLink>. Using the iChip, bacteria can be cultivated from vast sources, e.g., soil, seawater, wastewater and saliva <TextLink reference="27"></TextLink>. This technique has led scientists to discover over 25 new antibiotics and 10,00<TextGroup><PlainText>0 n</PlainText></TextGroup>ovel microbial species <TextLink reference="26"></TextLink>. Of these new antibiotics, clovibactin was found in a recently discovered organism termed <Mark2>Eleftheria terrae</Mark2> <TextLink reference="22"></TextLink>. Clovibactin is promising, as it can kill extremely drug-resistant bacteria and it has proved to protect mice from MRSA <TextLink reference="21"></TextLink>. The iChip is a hard plastic chip with nearly 200 wells <TextLink reference="26"></TextLink>. The unit is dipped into an agar laden with the bacterial sample in order to ensure that every well contains a cell <TextLink reference="26"></TextLink>. A diffusion membrane is positioned on the lateral sides of the chip and held with plastic tape to fix the bacteria in place <TextLink reference="26"></TextLink>, <TextLink reference="28"></TextLink>. The iChip, with its sample is placed back into the bacterium’s natural habitat (soil, bodies of water, etc.) where nutrients may pass through the diffusion membrane <TextLink reference="26"></TextLink>. This diffusion of growth factors across semi-permeable membranes supports uncultured bacteria growth (nearly 99% of all uncultured bacteria, in their natural habitat) <TextLink reference="28"></TextLink>.</Pgraph><Pgraph><Mark2>Eleftheria </Mark2>(<Mark2>E.</Mark2>) <Mark2>terrae</Mark2> belongs to the Eleftheria family, which includes the producer of another recently discovered antibiotic, teixobactin, and was isolated from soil in North Carolina (USA) <TextLink reference="29"></TextLink>. Colonies of this bacterium detected after 2.76 months of incubation were sub-cultured on nutrient agar plates spread with <Mark2>S. aureus</Mark2> and screened for antimicrobial activity <TextLink reference="19"></TextLink>. A clear zone of inhibition was observed around the <Mark2>E. terrae</Mark2>. Fractions of the extracts as identified by biological assays led to the isolation of a new depsipeptide molecule called NOVO-29 (clovibactin) <TextLink reference="19"></TextLink>, <TextLink reference="30"></TextLink>. </Pgraph><Pgraph><Mark2>E. terrae</Mark2> is capable of making more than one antibiotic (clovibactin, teixobactin and kalimantacin) <TextLink reference="19"></TextLink>. By means of high-pressure liquid chromatography (HPLC), part <TextGroup><PlainText>of the</PlainText></TextGroup> mixture capable of killing <Mark2>S. aureus</Mark2> and <Mark2>B. subtilis</Mark2> was identified and the genes of <Mark2>E. terrae</Mark2> were altered to focus on the production of clovibactin <TextLink reference="19"></TextLink>. The structure of clovibactin, as elucidated by NMR, was found to be similar to teixobactin in its molecular scaffold but with some important differences. It looks like a peptide, but has a mix of ester bonds and amino acids (hybrid) <TextLink reference="19"></TextLink>, <TextLink reference="30"></TextLink>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Staphylococcus aureus cell wall and antibiotics"> <MainHeadline>Staphylococcus aureus cell wall and antibiotics</MainHeadline><Pgraph>The discovery of clovibactin has been greeted as a step forward in the search for new therapeutic alternatives. Currently, knowledge of how this compound works is advancing through preclinical testing <TextLink reference="20"></TextLink>.</Pgraph><Pgraph>Peptidoglycan (PG) synthesis begins with the development of a molecule termed UDP-MurNAc, which is then connected with a pentapeptide section <TextLink reference="30"></TextLink>. This compound is joined with undecaprenyl pyrophosphate to make lipid I. Another molecule, UDP-GlcNAc, is joined to lipid I to produce lipid II. This entire progression happens within the cell membrane <TextLink reference="31"></TextLink>. lipid II is then transported perpendicularly through the membrane, where penicillin-binding proteins aid in building and reinforcing the cell wall by linking the PG subunits <TextLink reference="31"></TextLink>. The undecaprenyl pyrophosphate is returned to the cell for an additional cycle of use <TextLink reference="31"></TextLink>.</Pgraph><Pgraph>lipid II is susceptible to antibiotic attack when it is outside the bacterial membrane. Its design offers numerous targets for antibiotics, such as the pentapeptide domain (which vancomycin targets) or the pyrophosphate moiety targeted by other antibiotics, e.g., lantibiotics and ramoplanin <TextLink reference="32"></TextLink>. The quantity of lipid II in the cell membrane is small at any point in time, as it is rapidly consumed in cell-wall formation <TextLink reference="19"></TextLink>. Obstructing lipid II effectively (Figure 3 <ImgLink imgNo="3" imgType="figure"/>) stops the bacteria from constructing and re-inforcing their cell wall, resulting in their death <TextLink reference="19"></TextLink>.</Pgraph><Pgraph>The <Mark2>S. aureus</Mark2> cell is surrounded by strata of murein or PG, a tightly linked network composed of interconnected peptides and sugar molecules (β-(1–4)-N-acetyl hexosamine) <TextLink reference="33"></TextLink>. The mechanical strength of this layer aids the <Mark2>S. aureus</Mark2> bacterium to survive under adverse conditions, such as fluctuations in osmotic pressure <TextLink reference="33"></TextLink>. The more PG crosslinking there is in the bacterial wall, the more durable and stable the bacteria will be. This increased structural integrity and resilience makes the bacteria more resistant to external stressors and mechanical disruption <TextLink reference="33"></TextLink>, <TextLink reference="34"></TextLink>. The integrity of the PG layer is maintained by the enzymes trans glycosidase (which adds sugar peptides to elongate strands) and transpeptidase (links elongated strands together) <TextLink reference="33"></TextLink>. Because PG is crucial for maintaining the physical integrity of bacterial cell walls, it is an important target for many antibiotics, including those of the beta-lactam group and vancomycin <TextLink reference="33"></TextLink>.</Pgraph><Pgraph>Effective therapy with drugs that disturb the homoeostasis of cell-wall synthesis – for instance, glycopeptides and β-lactams – modifies cell structure and dimensions, causing stress inside the cell which ruptures it <TextLink reference="23"></TextLink> (<TextGroup><PlainText>Figure 1b </PlainText></TextGroup><ImgLink imgNo="1" imgType="figure"/>). β-lactams, such as penicillin, carbapenems and cephalosporins, prevent bacteria from assembling their cell walls <TextLink reference="21"></TextLink>. They do this by attaching to a part of the enzyme that facilitates cell-wall assembly (they block PG cross-linking), disabling the enzyme (penicillin binding proteins, PBPs) and causing the bacteria to cease growing <TextLink reference="22"></TextLink>.</Pgraph><Pgraph>The mechanism of action of glycopeptide antibiotics like vancomycin (which is derived from actinobacteria) differs substantially from that of β-lactams. Glycopeptide antibiotics se interrupt cell-wall maintenance by seizing <TextGroup><PlainText>onto a</PlainText></TextGroup> section of the PG edifice, to be exact, the D-alan<TextGroup><PlainText>yl-D-a</PlainText></TextGroup>lanine portion <TextLink reference="22"></TextLink>. This seizing action stops the enzymes transpeptidase and transglycosylase, which are vital for cell-wall assembly <TextLink reference="35"></TextLink>. As an effect, glycopeptides retard cell-wall construction and compromise the integrity of the cell wall <TextLink reference="36"></TextLink>. Unlike β-lactams (effective on Gram-positive and Gram-negative bacteria), glycopeptides are solely effective against Gram-positive bacteria, since they are not able permeate into Gram-negative bacteria <TextLink reference="19"></TextLink>. Also, other antibiotic types, such as Fosfomycin and Bacitracin, also disrupt different cell-wall maintenance processes <TextLink reference="19"></TextLink>.</Pgraph><Pgraph><Mark2>S. aureus</Mark2> possesses a lysis-toxin sensor regulator (LytSR) that can influence cell lysis by regulating the action of enzymes that decompose cell walls (autolysins) <TextLink reference="37"></TextLink>. LytSR activates genes such as the locus of reduced genome AB (LrgAB), which decelerate autolysins and increase the resistance of antibiotics <TextLink reference="38"></TextLink>. LrgA regulates how enzymes access the cell wall <TextLink reference="38"></TextLink>. Another system, termed “cell death-inducing cidAB” does the opposite, activating autolysins and making <Mark2>S. aureus</Mark2> easier to kill <TextLink reference="19"></TextLink>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Antibiotics’ mechanisms and clovibactin efficacy"> <MainHeadline>Antibiotics’ mechanisms and clovibactin efficacy</MainHeadline><Pgraph>Some studies have examined how antibiotics that halt cell wall construction can kill bacteria <TextLink reference="39"></TextLink>. At first, they assumed that these antibiotics triggered cell death by increasing pressure inside the cell to the extent that, when it grew faster than its walls, it ruptured <TextLink reference="40"></TextLink>. This was centred on the premise that protein synthesis was required for antibiotic-associated cell rupture. However, the machinery of cell death through lysis comprises active cellular processes such as poor amidase activity in, for instance, <Mark2>Streptococcus pneumoniae</Mark2>, leading to antibiotic tolerance. This highlights the role of autolysins in breaking down PG and contributing to lytic cell death in bacteria like <Mark2>Escherichia coli</Mark2> (<Mark2>E. coli</Mark2>), when coupled with cessation of PG synthesis by β-lactam antibiotics <TextLink reference="41"></TextLink>.</Pgraph><Pgraph>In susceptibility testing, the activity of clovibactin was good against <Mark2>S. aureus</Mark2> and its drug-resistant strains (DRSA, VISA, and MRSA) <TextLink reference="21"></TextLink>, <TextLink reference="22"></TextLink>. It was effective against vancomycin-resistant <Mark2>Enterococcus faecium</Mark2> and <Mark2>Enterococcus faecalis</Mark2> <TextLink reference="22"></TextLink>, but comparatively less effective against <Mark2>E. coli</Mark2>, due to the poor penetration efficacy of the compound <TextLink reference="22"></TextLink>, <TextLink reference="42"></TextLink>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Structure, targets, and efficacy"> <MainHeadline>Structure, targets, and efficacy</MainHeadline><Pgraph>Clovibactin is bactericidal against <Mark2>S. aureus</Mark2>, with an MBC (minimum bactericidal concentration) twice that of the MIC (minimum inhibitory concentration). When compared to vancomycin, its <Mark2>S. aureus </Mark2>killing effect is greater. Similar to teixobactin <TextLink reference="36"></TextLink>, it causes strong breakage of cell structure. Teixobactin molecules stick together and form pairs (hydrogen-bonded dimers). These pairs then group on the cell membrane in a β-sheet formation, causing important cell wall precursors to cluster, leading to the bacteria breaking apart. Likewise, clovibactin acts in a way that permits its side chains (Phenylalanine, Leucine and its isomer, D-Leucine) to insert into the cell membrane of <Mark2>S. aureus</Mark2>. Clovibactin molecules also stick together through hydrophobic interactions and hydrogen bonding, causing lipid II and related cell-wall precursors to cluster and the bacteria to break apart <TextLink reference="22"></TextLink>. Furthermore, unlike teixobactin, clovibactin could still lyse the cells even in the absence of <Mark2>AtlA</Mark2> protein <TextLink reference="42"></TextLink>.</Pgraph><Pgraph>To discover the target of clovibactin, first, the resistance frequency of <Mark2>S. aureus</Mark2> was determined to be lower than 10<Superscript>8</Superscript> (less than 10<Superscript>10</Superscript> was desirable) after an antimicrobial susceptibility assay of clovibactin-impregnated (less than four times the MIC) medium with <Mark2>S. aureus</Mark2> <TextLink reference="43"></TextLink>. There was no visible resistance, even at such a low concentration <TextLink reference="19"></TextLink>. This means the likelihood of drug resistance is less than one in ten billion. Knowledge of drug targets is very crucial for drug development, and understanding how often <Mark2>S. aureus</Mark2> may become resistant to a given drug ensures its clinical life-span <TextLink reference="43"></TextLink>. The biosynthetic pathway inhibited by clovibactin was traced using radiolabelled precursors injected into <Mark2>S. aureus</Mark2>. Of the major pathways of bacterial synthesis (PGs, Protein, RNA and DNA), clovibactin only prevented N-acetylglucosamine (GlcNAc) in the PG from being used in cell-wall synthesis <TextLink reference="19"></TextLink>.</Pgraph><Pgraph>To elucidate the specific effect of clovibactin, special tests were required to visualize temporal bacterial reactions. The <Mark2>LiaRS</Mark2> system responds to antibiotics that affect lipid II biosynthesis in the cell wall was utilized <TextLink reference="44"></TextLink>. LiaRS is a two-component regulatory system in <Mark2>S. aureus</Mark2>, consisting of a sensor kinase (LiaS) and a response regulator (LiaR), that is triggered when the bacterial respond to environmental stimuli. LiaRS is specifically activated by the presence of antibiotics targeting lipid II biosynthesis. The PliaI-lux test is an assay used to detect the activation of LiaRS via a bioluminescent reporter, allowing for the detection and quantification of LiaRS activi<TextGroup><PlainText>ty through b</PlainText></TextGroup>ioluminescence measurements. Clovibactin trigger<TextGroup><PlainText>ed a p</PlainText></TextGroup>ositive reaction in the PliaI-lux test, in which light emission signifies the activation of the <Mark2>LiaI</Mark2> promoter, indicative of its direct effect on the lipid II biosynthesis <TextLink reference="22"></TextLink>, <TextLink reference="45"></TextLink>.</Pgraph><Pgraph>In the <Mark2>S. aureus</Mark2> cytoplasm, the nucleotide sugars UDP-GlcNAc and UDP-N-acetylmuramic acid are biosynthesized <TextLink reference="33"></TextLink>. These sugars are then bound to a lipid carrier known as undecaprenyl phosphate (C55P) to form lipid II <TextLink reference="33"></TextLink>. This lipid is added to a branching network of PG in cell-wall synthesis. Clovibactin might work by preventing the occurrence of this later stage, resulting in the intracellular build-up UDP-GlcNAc and UDP-N-acetylmuramic acid, which will eventually lead to the death of the bacterial cell <TextLink reference="33"></TextLink>.</Pgraph><Pgraph>Clovibactin stops the cell wall from performing processes that use the building blocks (lipids I, II, IIIWTA, or C55PP) as a reactant in a stepwise manner. This indicates that clovibactin does not stop enzyme function, but rather, it attaches itself to these reactants, indicating that these building blocks are the major target of the molecule <TextLink reference="42"></TextLink>.</Pgraph><Pgraph>Scientists use solid-state NMR to visualize how clovibactin engages with lipid II within the cell membranes <TextLink reference="21"></TextLink>, <TextLink reference="30"></TextLink>. The antibiotic is radiolabelled to enhance its tracking. The interaction of clovibactin and llipid II results in clear ssNMR spectra of a stable clovibactin-lipid II complex. Clovibactin changes its conformation shape markedly when it bound to lipid II, suggesting it undergoes major structural alterations <TextLink reference="21"></TextLink>, <TextLink reference="30"></TextLink>, <TextLink reference="42"></TextLink>. </Pgraph><Pgraph>Coupled with ssNMR spectra, the confocal microscopic visualization of the clovibactin-lipid II complex elucidated large (supramolecular) structures <TextLink reference="22"></TextLink>. The visualization showed that the anterior part of clovibactin became stiffer when it merged with lipid II, suggesting that it behaved like teixobactin, and further revealed giant unilamellar vesicles, or GUVs (balloon-like) structures, with large clusters of clovibactin-lipid II structures on their surface <TextLink reference="22"></TextLink>, <TextLink reference="36"></TextLink>. </Pgraph></TextBlock> <TextBlock linked="yes" name="Analogues"> <MainHeadline>Analogues</MainHeadline><Pgraph>The discovery of clovibactin is thrilling since it promises fresh ways to fight bacteria, but development and improvement may be sluggish, as it is difficult to produce <TextLink reference="22"></TextLink>. Making clovibactin is very labour-intensive and yields only a minor quantity <TextLink reference="22"></TextLink>, <TextLink reference="35"></TextLink>. Researchers are working on simpler versions of clovibactin and other depsipeptides to make production easier without losing its bactericidal action <TextLink reference="40"></TextLink>, <TextLink reference="42"></TextLink>. Effective approaches to produce analogues may include methods that employ commercially available building blocks, require a mono-purification step, and produce a good yield. Clovibactin is one of the robust antibiotics that did not originate from conventional ribosomal protein-making processes and use D-amino acids. Other examples are teixobactin, vancomycin and polymyxin. Attention should be given to the high price of developing new antibiotics like clovibactin. Trial phases 1 and 3 may entail up to ten million dollars and a critical phase 3 trial can be five times as expensive <TextLink reference="36"></TextLink>, <TextLink reference="46"></TextLink>. There are already several drugs commercially available to treat MRSA, e.g., linezolid, daptomycin, clindamyci<TextGroup><PlainText>n, c</PlainText></TextGroup>eftaroline and doxycycline <TextLink reference="47"></TextLink>, <TextLink reference="48"></TextLink>. A new drug, even one as auspicious as clovibactin, has to offer something unique to be worth its high price. In addition to inexpensive oral and intravenous options, there is also a growing market for injectable drugs (e.g., dalbavancin), which can be administered in a single dose and be effective for a lengthy period <TextLink reference="49"></TextLink>. However, some new MRSA drugs cost thousands of dollars per dose, and hospitals are unwilling to add such expensive drugs to their already strained budgets <TextLink reference="36"></TextLink>.</Pgraph><Pgraph>When compared to MRSA, evidence suggests that there is more attention to developing new drugs to treat resistant gram-negative infectio<TextGroup><PlainText>ns (e.g., </PlainText><Mark2>Klebsiella pn</Mark2></TextGroup><Mark2>eumon</Mark2><TextGroup><Mark2>i</Mark2></TextGroup><Mark2>ae</Mark2>). While there are many successful trials on Gram-negative infections, comparable studies for MRSA are wanting <TextLink reference="50"></TextLink>. Clovibactin is a more recent discovery than malacidin and teixobactin, which are further along in development, but both face challenges as human trials are lacking. These new anti MRSA drugs are difficult to produce on a large scale and their development costs billions of dollars <TextLink reference="46"></TextLink>. </Pgraph><Pgraph>While these drugs are promising, incorporating these new products into an already full market is difficult. Weighing the costs and benefits of new antibiotics plays a significant role in aiding hospitals to choose the best antibiotics in terms of both patient care and funds. Finding less toxic and expensive derivatives of clovibactin effective against MRSA and even across the spectrum to Gram-negative bacteria would be ideal.</Pgraph><Pgraph>Needless to say, researchers are already trying to modify clovibactin to fashion an even more active compound. In the years ahead, these novel molecules will receive great attention. Healthcare providers often realise the limits of existing antibiotics, as many patients are not able to tolerate them.</Pgraph><Pgraph>Future research (Figure 4 <ImgLink imgNo="4" imgType="figure"/>) on clovibactin will center on the use of innovative technology, such as fermentation processes and synthetic biology, to increase efforts and meet the necessities of hospitals and patients. It is of paramount importance to find new antibiotics, advance old ones, and produce them in new ways, mainly to target threatening bacteria such as <Mark2>S. aureus</Mark2> and its resistant strains. </Pgraph><Pgraph>The scientific community strives to combat diverse diseases by determining how antibiotics function and producing better treatments. A good illustration of this is the increasing understanding of the new paths by which bacteria obtain resistance to drugs and discovering new means to stop or slow these phenomena. Work is being done on designing new drugs to develop safer, non-toxic antibiotics that are effective against both metabolically active and dormant bacteria using technologies, such as deep learning, generative AI, metagenomics, iChip technology, synthetic biology, CRISPR-Cas9 screening, high-throughput screening, exploring extremophiles, and phage therapy and lysins. Critically assessing past achievements and disappointments in antibiotic discovery will help advance future research. Another thematic focus is biofilms and searching for ways to destroy them for better therapeutic outcome. </Pgraph><Pgraph>Overcoming hurdles such as stringent regulations, costs, and the labour-intensive development of novel drugs requires interdisciplinary collaboration and new methodologies.</Pgraph></TextBlock> <TextBlock linked="yes" name="Conclusion and future directions"> <MainHeadline>Conclusion and future directions</MainHeadline><Pgraph>The antibiotic clovibactin is a new depsipeptide which is highly efficacious against <Mark2>S. aureus</Mark2> and its drug-resistant strains. It represents a ground-breaking advancement in antibiotic discovery. Its molecular structure, unique mechanism of action and bactericidal ability (targeting the lipid II biosynthesis pathway) make it a good choice as a promising candidate for developing new antibiotics and treating unresponsive infections. Future research work should focus on design and synthesis of highly potent clovibactin analogues against <Mark2>S. aureus</Mark2>, methicillin-resistant (MRSA) and vancomycin-resistant (VRSA) <Mark2>S. aureus</Mark2>; total synthesis of clovibactin; the use of clovibactin as a scaffold for unlimited new antimicrobial peptides; in-vitro antibacterial activity of clovibactin and possible analogues against MRSA and other clinical bacterial Isolates; further investigations into its killing mechanism against MRSA; and exploring the likelihood of de novo resistance to clovibactin. Continued research and innovative approaches are essential to safeguard these vital medicines and address the growing threat of antibiotic resistance.</Pgraph></TextBlock> <TextBlock linked="yes" name="Notes"> <MainHeadline>Notes</MainHeadline><SubHeadline>Author’s ORCID </SubHeadline><Pgraph><UnorderedList><ListItem level="1">Adeiza Shuaibu Suleiman: <Hyperlink href="https://orcid.org/0000-0002-9293-2600">0000-0002-9293-2600</Hyperlink></ListItem></UnorderedList></Pgraph><SubHeadline>Funding </SubHeadline><Pgraph>None.</Pgraph><SubHeadline>Competing interests</SubHeadline><Pgraph>The author affirms that he has no competing interests.</Pgraph></TextBlock> <References linked="yes"> <Reference refNo="1"> <RefAuthor>Halawa EM</RefAuthor> <RefAuthor>Fadel M</RefAuthor> <RefAuthor>Al-Rabia MW</RefAuthor> <RefAuthor>Behairy A</RefAuthor> <RefAuthor>Nouh NA</RefAuthor> <RefAuthor>Abdo M</RefAuthor> <RefAuthor>Olga R</RefAuthor> <RefAuthor>Fericean L</RefAuthor> <RefAuthor>Atwa AM</RefAuthor> <RefAuthor>El-Nablaway M</RefAuthor> <RefAuthor>Abdeen A</RefAuthor> <RefTitle>Antibiotic action and resistance: updated review of mechanisms, spread, influencing factors, and alternative approaches for combating resistance</RefTitle> <RefYear>2023</RefYear> <RefJournal>Front Pharmacol</RefJournal> <RefPage>1305294</RefPage> <RefTotal>Halawa EM, Fadel M, Al-Rabia MW, Behairy A, Nouh NA, Abdo M, Olga R, Fericean L, Atwa AM, El-Nablaway M, Abdeen A. Antibiotic action and resistance: updated review of mechanisms, spread, influencing factors, and alternative approaches for combating resistance. Front Pharmacol. 2023;14:1305294. DOI: 10.3389/fphar.2023.1305294</RefTotal> <RefLink>https://doi.org/10.3389/fphar.2023.1305294</RefLink> </Reference> <Reference refNo="2"> <RefAuthor>Baquero F</RefAuthor> <RefAuthor>Rodríguez-Beltrán J</RefAuthor> <RefAuthor>Levin BR</RefAuthor> <RefTitle>Bacteriostatic cells instead of bacteriostatic antibiotics?</RefTitle> <RefYear>2024</RefYear> <RefJournal>mBio</RefJournal> <RefPage>e0268023</RefPage> <RefTotal>Baquero F, Rodríguez-Beltrán J, Levin BR. Bacteriostatic cells instead of bacteriostatic antibiotics? mBio. 2024 Feb;15(2):e0268023. DOI: 10.1128/mbio.02680-23</RefTotal> <RefLink>https://doi.org/10.1128/mbio.02680-23</RefLink> </Reference> <Reference refNo="3"> <RefAuthor>Zheng EJ</RefAuthor> <RefAuthor>Valeri JA</RefAuthor> <RefAuthor>Andrews IW</RefAuthor> <RefAuthor>Krishnan A</RefAuthor> <RefAuthor>Bandyopadhyay P</RefAuthor> <RefAuthor>Anahtar MN</RefAuthor> <RefAuthor>Herneisen A</RefAuthor> <RefAuthor>Schulte F</RefAuthor> <RefAuthor>Linnehan B</RefAuthor> <RefAuthor>Wong F</RefAuthor> <RefAuthor>Stokes JM</RefAuthor> <RefAuthor>Renner LD</RefAuthor> <RefAuthor>Lourido S</RefAuthor> <RefAuthor>Collins JJ</RefAuthor> <RefTitle>Discovery of antibiotics that selectively kill metabolically dormant bacteria</RefTitle> <RefYear>2024</RefYear> <RefJournal>Cell Chem Biol</RefJournal> <RefPage>712-28</RefPage> <RefTotal>Zheng EJ, Valeri JA, Andrews IW, Krishnan A, Bandyopadhyay P, Anahtar MN, Herneisen A, Schulte F, Linnehan B, Wong F, Stokes JM, Renner LD, Lourido S, Collins JJ. Discovery of antibiotics that selectively kill metabolically dormant bacteria. Cell Chem Biol. 2024 Apr;31(4):712-28.e9. DOI: 10.1016/j.chembiol.2023.10.026</RefTotal> <RefLink>https://doi.org/10.1016/j.chembiol.2023.10.026</RefLink> </Reference> <Reference refNo="4"> <RefAuthor>Zhang T</RefAuthor> <RefAuthor>Liu Q</RefAuthor> <RefAuthor>Meng F</RefAuthor> <RefAuthor>Hou Y</RefAuthor> <RefAuthor>Leung MKH</RefAuthor> <RefAuthor>Wen Y</RefAuthor> <RefAuthor>Zhang Q</RefAuthor> <RefTitle>Recent advances in stimuli-responsive antibacterial coatings: Bacteria-killing and releasing mechanism, design strategies, and potential applications</RefTitle> <RefYear>2024</RefYear> <RefJournal>Prog Org Coat</RefJournal> <RefPage>107923</RefPage> <RefTotal>Zhang T, Liu Q, Meng F, Hou Y, Leung MKH, Wen Y, Zhang Q. Recent advances in stimuli-responsive antibacterial coatings: Bacteria-killing and releasing mechanism, design strategies, and potential applications. Prog Org Coat. 2024; 186:107923. DOI: 10.1016/j.porgcoat.2023.107923</RefTotal> <RefLink>https://doi.org/10.1016/j.porgcoat.2023.107923</RefLink> </Reference> <Reference refNo="5"> <RefAuthor>Halawa EM</RefAuthor> <RefAuthor>Fadel M</RefAuthor> <RefAuthor>Al-Rabia MW</RefAuthor> <RefAuthor>Behairy A</RefAuthor> <RefAuthor>Nouh NA</RefAuthor> <RefAuthor>Abdo M</RefAuthor> <RefAuthor>Olga R</RefAuthor> <RefAuthor>Fericean L</RefAuthor> <RefAuthor>Atwa AM</RefAuthor> <RefAuthor>El-Nablaway M</RefAuthor> <RefAuthor>Abdeen A</RefAuthor> <RefTitle>Antibiotic action and resistance: updated review of mechanisms, spread, influencing factors, and alternative approaches for combating resistance</RefTitle> <RefYear>2023</RefYear> <RefJournal>Front Pharmacol</RefJournal> <RefPage>1305294</RefPage> <RefTotal>Halawa EM, Fadel M, Al-Rabia MW, Behairy A, Nouh NA, Abdo M, Olga R, Fericean L, Atwa AM, El-Nablaway M, Abdeen A. Antibiotic action and resistance: updated review of mechanisms, spread, influencing factors, and alternative approaches for combating resistance. Front Pharmacol. 2023;14:1305294. DOI: 10.3389/fphar.2023.1305294</RefTotal> <RefLink>https://doi.org/10.3389/fphar.2023.1305294</RefLink> </Reference> <Reference refNo="6"> <RefAuthor>Durand GA</RefAuthor> <RefAuthor>Raoult D</RefAuthor> <RefAuthor>Dubourg G</RefAuthor> <RefTitle>Antibiotic discovery: history, methods and perspectives</RefTitle> <RefYear>2019</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>371-82</RefPage> <RefTotal>Durand GA, Raoult D, Dubourg G. Antibiotic discovery: history, methods and perspectives. Int J Antimicrob Agents. 2019 Apr;53(4):371-82. DOI: 10.1016/j.ijantimicag.2018.11.010</RefTotal> <RefLink>https://doi.org/10.1016/j.ijantimicag.2018.11.010</RefLink> </Reference> <Reference refNo="7"> <RefAuthor>Meštrović T</RefAuthor> <RefAuthor>Ikuta KS</RefAuthor> <RefAuthor>Swetschinski L</RefAuthor> <RefAuthor>Gray A</RefAuthor> <RefAuthor>Aguilar GR</RefAuthor> <RefAuthor>Han C</RefAuthor> <RefAuthor>Wool E</RefAuthor> <RefAuthor>Gershberg Hayoon A</RefAuthor> <RefAuthor>Murray CJL</RefAuthor> <RefAuthor>Naghavi M</RefAuthor> <RefTitle>The burden of bacterial antimicrobial resistance in Croatia in 2019: a country-level systematic analysis</RefTitle> <RefYear>2023</RefYear> <RefJournal>Croat Med J</RefJournal> <RefPage>272–83</RefPage> <RefTotal>Meštrović T, Ikuta KS, Swetschinski L, Gray A, Aguilar GR, Han C, Wool E, Gershberg Hayoon A, Murray CJL, Naghavi M. The burden of bacterial antimicrobial resistance in Croatia in 2019: a country-level systematic analysis. Croat Med J. 2023;64(4):272–83. DOI: 10.3325/cmj.2023.64.272</RefTotal> <RefLink>https://doi.org/10.3325/cmj.2023.64.272</RefLink> </Reference> <Reference refNo="8"> <RefAuthor>Sartorius B</RefAuthor> <RefAuthor>Gray AP</RefAuthor> <RefAuthor>Davis Weaver N</RefAuthor> <RefAuthor>Robles Aguilar G</RefAuthor> <RefAuthor>Swetschinski LR</RefAuthor> <RefAuthor>Ikuta KS</RefAuthor> <RefTitle>The burden of bacterial antimicrobial resistance in the WHO African region in 2019: a cross-country systematic analysis</RefTitle> <RefYear>2024</RefYear> <RefJournal>Lancet Glob Health</RefJournal> <RefPage>e201-e216</RefPage> <RefTotal>Sartorius B, Gray AP, Davis Weaver N, Robles Aguilar G, Swetschinski LR, Ikuta KS et al. The burden of bacterial antimicrobial resistance in the WHO African region in 2019: a cross-country systematic analysis. Lancet Glob Health. 2024 Feb;12(2):e201-e216. DOI: 10.1016/S2214-109X(23)00539-9</RefTotal> <RefLink>https://doi.org/10.1016/S2214-109X(23)00539-9</RefLink> </Reference> <Reference refNo="9"> <RefAuthor>Tang KWK</RefAuthor> <RefAuthor>Millar BC</RefAuthor> <RefAuthor>Moore JE</RefAuthor> <RefTitle>Antimicrobial Resistance (AMR)</RefTitle> <RefYear>2023</RefYear> <RefJournal>Br J Biomed Sci</RefJournal> <RefPage>11387</RefPage> <RefTotal>Tang KWK, Millar BC, Moore JE. Antimicrobial Resistance (AMR). Br J Biomed Sci. 2023;80:11387. DOI: 10.3389/bjbs.2023.11387</RefTotal> <RefLink>https://doi.org/10.3389/bjbs.2023.11387</RefLink> </Reference> <Reference refNo="10"> <RefAuthor>Liu K</RefAuthor> <RefAuthor>Wang C</RefAuthor> <RefAuthor>Zhou X</RefAuthor> <RefAuthor>Guo X</RefAuthor> <RefAuthor>Yang Y</RefAuthor> <RefAuthor>Liu W</RefAuthor> <RefAuthor>Zhao R</RefAuthor> <RefAuthor>Song H</RefAuthor> <RefTitle>Bacteriophage therapy for drug-resistant infections</RefTitle> <RefYear>2024</RefYear> <RefJournal>Front Cell Infect Microbiol</RefJournal> <RefPage>1336821</RefPage> <RefTotal>Liu K, Wang C, Zhou X, Guo X, Yang Y, Liu W, Zhao R, Song H. Bacteriophage therapy for drug-resistant infections. Front Cell Infect Microbiol. 2024;14:1336821. DOI: 10.3389/fcimb.2024.1336821</RefTotal> <RefLink>https://doi.org/10.3389/fcimb.2024.1336821</RefLink> </Reference> <Reference refNo="11"> <RefAuthor>Adeiza SS</RefAuthor> <RefAuthor>Shuaibu AB</RefAuthor> <RefAuthor>Shuaibu GM</RefAuthor> <RefTitle>Random effects meta-analysis of COVID-19/S. aureus partnership in co-infection</RefTitle> <RefYear>2020</RefYear> <RefJournal>GMS Hyg Infect Control</RefJournal> <RefPage>Doc29</RefPage> <RefTotal>Adeiza SS, Shuaibu AB, Shuaibu GM. Random effects meta-analysis of COVID-19/S. aureus partnership in co-infection. GMS Hyg Infect Control. 2020;15:Doc29. DOI: 10.3205/dgkh000364</RefTotal> <RefLink>https://doi.org/10.3205/dgkh000364</RefLink> </Reference> <Reference refNo="12"> <RefAuthor>Adeiza SS</RefAuthor> <RefAuthor>Aminul I</RefAuthor> <RefTitle>Meta-meta-analysis of the mortality risk associated with MRSA compared to MSSA bacteraemia</RefTitle> <RefYear>2024</RefYear> <RefJournal>Infezioni in Medicina</RefJournal> <RefPage></RefPage> <RefTotal>Adeiza SS, Aminul I. Meta-meta-analysis of the mortality risk associated with MRSA compared to MSSA bacteraemia. Infezioni in Medicina. 2024;32(2). DOI: 10.53854/liim-3202-2</RefTotal> <RefLink>https://doi.org/10.53854/liim-3202-2</RefLink> </Reference> <Reference refNo="13"> <RefAuthor>Antimicrobial Resistance Collaborators</RefAuthor> <RefTitle>Correction to “The burden of antimicrobial resistance in the Americas in 2019: a cross-country systematic analysis” The Lancet Regional Health—Americas 2023; 25, 100561</RefTitle> <RefYear>2023</RefYear> <RefJournal>Lancet Reg Health Am</RefJournal> <RefPage>100632</RefPage> <RefTotal>Antimicrobial Resistance Collaborators. Correction to “The burden of antimicrobial resistance in the Americas in 2019: a cross-country systematic analysis” The Lancet Regional Health—Americas 2023; 25, 100561. Lancet Reg Health Am. 2023 Dec;28:100632. DOI: 10.1016/j.lana.2023.100632</RefTotal> <RefLink>https://doi.org/10.1016/j.lana.2023.100632</RefLink> </Reference> <Reference refNo="14"> <RefAuthor>Gopikrishnan M</RefAuthor> <RefAuthor>Haryini S</RefAuthor> <RefAuthor>C GPD</RefAuthor> <RefTitle>Emerging strategies and therapeutic innovations for combating drug resistance in Staphylococcus aureus strains: A comprehensive review</RefTitle> <RefYear>2024</RefYear> <RefJournal>J Basic Microbiol</RefJournal> <RefPage>e2300579</RefPage> <RefTotal>Gopikrishnan M, Haryini S, C GPD. Emerging strategies and therapeutic innovations for combating drug resistance in Staphylococcus aureus strains: A comprehensive review. J Basic Microbiol. 2024 May;64(5):e2300579. DOI: 10.1002/jobm.202300579</RefTotal> <RefLink>https://doi.org/10.1002/jobm.202300579</RefLink> </Reference> <Reference refNo="15"> <RefAuthor>Rahimkhani M</RefAuthor> <RefAuthor>Rajabi Z</RefAuthor> <RefTitle>MRSA and VRSA isolated from patients hospitalized in the ICU, NICU and surgical departments of hospitals</RefTitle> <RefYear>2024</RefYear> <RefJournal>Proc Natl Acad Sci, India, Sect B Biol Sci</RefJournal> <RefPage>53-7</RefPage> <RefTotal>Rahimkhani M, Rajabi Z. MRSA and VRSA isolated from patients hospitalized in the ICU, NICU and surgical departments of hospitals. Proc Natl Acad Sci, India, Sect B Biol Sci. 2024:53-7. DOI: 10.1007/s40011-024-01558-8</RefTotal> <RefLink>https://doi.org/10.1007/s40011-024-01558-8</RefLink> </Reference> <Reference refNo="16"> <RefAuthor>Suleiman AS</RefAuthor> <RefAuthor>Ademola OJ</RefAuthor> <RefAuthor>Olalekan OB</RefAuthor> <RefTitle>Constellation of methicillin-resistant genomic islands (SCCmec) among nasal meticillin-resistant Staphylococcus aureus isolates</RefTitle> <RefYear>2021</RefYear> <RefJournal>Acta Facultatis Medicae Naissensis</RefJournal> <RefPage>360-70</RefPage> <RefTotal>Suleiman AS, Ademola OJ, Olalekan OB. Constellation of methicillin-resistant genomic islands (SCCmec) among nasal meticillin-resistant Staphylococcus aureus isolates. Acta Facultatis Medicae Naissensis. 2021;38(4):360-70. DOI: 10.5937/afmnai38-25349</RefTotal> <RefLink>https://doi.org/10.5937/afmnai38-25349</RefLink> </Reference> <Reference refNo="17"> <RefAuthor>Adamu Y</RefAuthor> <RefAuthor>Puig-Asensio M</RefAuthor> <RefAuthor>Dabo B</RefAuthor> <RefAuthor>Schweizer ML</RefAuthor> <RefTitle>Comparative effectiveness of daptomycin versus vancomycin among patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections: A systematic literature review and meta-analysis</RefTitle> <RefYear>2024</RefYear> <RefJournal>PLoS One</RefJournal> <RefPage>e0293423</RefPage> <RefTotal>Adamu Y, Puig-Asensio M, Dabo B, Schweizer ML. Comparative effectiveness of daptomycin versus vancomycin among patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections: A systematic literature review and meta-analysis. PLoS One. 2024;19(2):e0293423. DOI: 10.1371/journal.pone.0293423</RefTotal> <RefLink>https://doi.org/10.1371/journal.pone.0293423</RefLink> </Reference> <Reference refNo="18"> <RefAuthor>Nazli A</RefAuthor> <RefAuthor>Tao W</RefAuthor> <RefAuthor>You H</RefAuthor> <RefAuthor>He X</RefAuthor> <RefAuthor>He Y</RefAuthor> <RefTitle>Treatment of MRSA Infection: Where are We?</RefTitle> <RefYear>2024</RefYear> <RefJournal>Curr Med Chem</RefJournal> <RefPage>4425-60</RefPage> <RefTotal>Nazli A, Tao W, You H, He X, He Y. Treatment of MRSA Infection: Where are We? Curr Med Chem. 2024;31(28):4425-60. DOI: 10.2174/0109298673249381231130111352</RefTotal> <RefLink>https://doi.org/10.2174/0109298673249381231130111352</RefLink> </Reference> <Reference refNo="19"> <RefAuthor>Shukla R</RefAuthor> <RefAuthor>Peoples AJ</RefAuthor> <RefAuthor>Ludwig KC</RefAuthor> <RefAuthor>Maity S</RefAuthor> <RefAuthor>Derks MGN</RefAuthor> <RefAuthor>De Benedetti S</RefAuthor> <RefAuthor>Krueger AM</RefAuthor> <RefAuthor>Vermeulen BJA</RefAuthor> <RefAuthor>Harbig T</RefAuthor> <RefAuthor>Lavore F</RefAuthor> <RefAuthor>Kumar R</RefAuthor> <RefAuthor>Honorato RV</RefAuthor> <RefAuthor>Grein F</RefAuthor> <RefAuthor>Nieselt K</RefAuthor> <RefAuthor>Liu Y</RefAuthor> <RefAuthor>Bonvin AMJJ</RefAuthor> <RefAuthor>Baldus M</RefAuthor> <RefAuthor>Kubitscheck U</RefAuthor> <RefAuthor>Breukink E</RefAuthor> <RefAuthor>Achorn C</RefAuthor> <RefAuthor>Nitti A</RefAuthor> <RefAuthor>Schwalen CJ</RefAuthor> <RefAuthor>Spoering AL</RefAuthor> <RefAuthor>Ling LL</RefAuthor> <RefAuthor>Hughes D</RefAuthor> <RefAuthor>Lelli M</RefAuthor> <RefAuthor>Roos WH</RefAuthor> <RefAuthor>Lewis K</RefAuthor> <RefAuthor>Schneider T</RefAuthor> <RefAuthor>Weingarth M</RefAuthor> <RefTitle>An antibiotic from an uncultured bacterium binds to an immutable target</RefTitle> <RefYear>2023</RefYear> <RefJournal>Cell</RefJournal> <RefPage>4059-73</RefPage> <RefTotal>Shukla R, Peoples AJ, Ludwig KC, Maity S, Derks MGN, De Benedetti S, Krueger AM, Vermeulen BJA, Harbig T, Lavore F, Kumar R, Honorato RV, Grein F, Nieselt K, Liu Y, Bonvin AMJJ, Baldus M, Kubitscheck U, Breukink E, Achorn C, Nitti A, Schwalen CJ, Spoering AL, Ling LL, Hughes D, Lelli M, Roos WH, Lewis K, Schneider T, Weingarth M. An antibiotic from an uncultured bacterium binds to an immutable target. Cell. 2023 Sep;186(19):4059-73.e27. DOI: 10.1016/j.cell.2023.07.038</RefTotal> <RefLink>https://doi.org/10.1016/j.cell.2023.07.038</RefLink> </Reference> <Reference refNo="20"> <RefAuthor>Bratovič M</RefAuthor> <RefTitle>An antibacterial glove</RefTitle> <RefYear>2023</RefYear> <RefJournal>Nat Chem Biol</RefJournal> <RefPage>1290</RefPage> <RefTotal>Bratovič M. An antibacterial glove. Nat Chem Biol. 2023 Nov;19(11):1290. DOI: 10.1038/s41589-023-01469-1</RefTotal> <RefLink>https://doi.org/10.1038/s41589-023-01469-1</RefLink> </Reference> <Reference refNo="21"> <RefAuthor>Le Page M</RefAuthor> <RefTitle>Antibiotic clovibactin kills even the superbugs that are resistant to drugs</RefTitle> <RefYear>2023</RefYear> <RefJournal>New Scientist</RefJournal> <RefPage>10</RefPage> <RefTotal>Le Page M. Antibiotic clovibactin kills even the superbugs that are resistant to drugs. New Scientist. 2023;258(3442):10. DOI: 10.1016/s0262-4079(23)01023-0</RefTotal> <RefLink>https://doi.org/10.1016/s0262-4079(23)01023-0</RefLink> </Reference> <Reference refNo="22"> <RefAuthor>Pérez-Moreno AM</RefAuthor> <RefAuthor>Torres P</RefAuthor> <RefAuthor>Paris JL</RefAuthor> <RefTitle>Clovibactin: Discovery and antimicrobial mechanism of action</RefTitle> <RefYear>2024</RefYear> <RefJournal>Allergy</RefJournal> <RefPage>2302-4</RefPage> <RefTotal>Pérez-Moreno AM, Torres P, Paris JL. Clovibactin: Discovery and antimicrobial mechanism of action. Allergy. 2024 Aug;79(8):2302-4. DOI: 10.1111/all.16144</RefTotal> <RefLink>https://doi.org/10.1111/all.16144</RefLink> </Reference> <Reference refNo="23"> <RefAuthor>Buijs NP</RefAuthor> <RefAuthor>Matheson EJ</RefAuthor> <RefAuthor>Cochrane SA</RefAuthor> <RefAuthor>Martin NI</RefAuthor> <RefTitle>Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic</RefTitle> <RefYear>2023</RefYear> <RefJournal>Chem Commun (Camb)</RefJournal> <RefPage>7685-703</RefPage> <RefTotal>Buijs NP, Matheson EJ, Cochrane SA, Martin NI. Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic. Chem Commun (Camb). 2023 Jun;59(50):7685-703. DOI: 10.1039/d3cc01070h</RefTotal> <RefLink>https://doi.org/10.1039/d3cc01070h</RefLink> </Reference> <Reference refNo="24"> <RefAuthor>Fage CD</RefAuthor> <RefAuthor>Lathouwers T</RefAuthor> <RefAuthor>Vanmeert M</RefAuthor> <RefAuthor>Gao LJ</RefAuthor> <RefAuthor>Vrancken K</RefAuthor> <RefAuthor>Lammens EM</RefAuthor> <RefAuthor>Weir ANM</RefAuthor> <RefAuthor>Degroote R</RefAuthor> <RefAuthor>Cuppens H</RefAuthor> <RefAuthor>Kosol S</RefAuthor> <RefAuthor>Simpson TJ</RefAuthor> <RefAuthor>Crump MP</RefAuthor> <RefAuthor>Willis CL</RefAuthor> <RefAuthor>Herdewijn P</RefAuthor> <RefAuthor>Lescrinier E</RefAuthor> <RefAuthor>Lavigne R</RefAuthor> <RefAuthor>Anné J</RefAuthor> <RefAuthor>Masschelein J</RefAuthor> <RefTitle>The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI</RefTitle> <RefYear>2020</RefYear> <RefJournal>Angew Chem Int Ed Engl</RefJournal> <RefPage>10549-56</RefPage> <RefTotal>Fage CD, Lathouwers T, Vanmeert M, Gao LJ, Vrancken K, Lammens EM, Weir ANM, Degroote R, Cuppens H, Kosol S, Simpson TJ, Crump MP, Willis CL, Herdewijn P, Lescrinier E, Lavigne R, Anné J, Masschelein J. The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI. Angew Chem Int Ed Engl. 2020 Jun;59(26):10549-56. DOI: 10.1002/anie.201915407</RefTotal> <RefLink>https://doi.org/10.1002/anie.201915407</RefLink> </Reference> <Reference refNo="25"> <RefAuthor>Quinn GA</RefAuthor> <RefAuthor>Dyson PJ</RefAuthor> <RefTitle>Going to extremes: progress in exploring new environments for novel antibiotics</RefTitle> <RefYear>2024</RefYear> <RefJournal>NPJ Antimicrob Resist</RefJournal> <RefPage>1-9</RefPage> <RefTotal>Quinn GA, Dyson PJ. Going to extremes: progress in exploring new environments for novel antibiotics. NPJ Antimicrob Resist. 2024;2(1):1-9. DOI: 10.1038/s44259-024-00025-8</RefTotal> <RefLink>https://doi.org/10.1038/s44259-024-00025-8</RefLink> </Reference> <Reference refNo="26"> <RefAuthor>Berdy B</RefAuthor> <RefAuthor>Spoering AL</RefAuthor> <RefAuthor>Ling LL</RefAuthor> <RefAuthor>Epstein SS</RefAuthor> <RefTitle>In situ cultivation of previously uncultivable microorganisms using the ichip</RefTitle> <RefYear>2017</RefYear> <RefJournal>Nat Protoc</RefJournal> <RefPage>2232-42</RefPage> <RefTotal>Berdy B, Spoering AL, Ling LL, Epstein SS. In situ cultivation of previously uncultivable microorganisms using the ichip. Nat Protoc. 2017 Oct;12(10):2232-42. DOI: 10.1038/nprot.2017.074</RefTotal> <RefLink>https://doi.org/10.1038/nprot.2017.074</RefLink> </Reference> <Reference refNo="27"> <RefAuthor>Nichols D</RefAuthor> <RefAuthor>Cahoon N</RefAuthor> <RefAuthor>Trakhtenberg EM</RefAuthor> <RefAuthor>Pham L</RefAuthor> <RefAuthor>Mehta A</RefAuthor> <RefAuthor>Belanger A</RefAuthor> <RefAuthor>Kanigan T</RefAuthor> <RefAuthor>Lewis K</RefAuthor> <RefAuthor>Epstein SS</RefAuthor> <RefTitle>Use of ichip for high-throughput in situ cultivation of “uncultivable” microbial species</RefTitle> <RefYear>2010</RefYear> <RefJournal>Appl Environ Microbiol</RefJournal> <RefPage>2445-50</RefPage> <RefTotal>Nichols D, Cahoon N, Trakhtenberg EM, Pham L, Mehta A, Belanger A, Kanigan T, Lewis K, Epstein SS. Use of ichip for high-throughput in situ cultivation of “uncultivable” microbial species. Appl Environ Microbiol. 2010 Apr;76(8):2445-50. DOI: 10.1128/AEM.01754-09</RefTotal> <RefLink>https://doi.org/10.1128/AEM.01754-09</RefLink> </Reference> <Reference refNo="28"> <RefAuthor>Li C</RefAuthor> <RefAuthor>Ouyang Z</RefAuthor> <RefAuthor>Liu J</RefAuthor> <RefTitle>Chapter 9 - Bacterial growth and cultivation</RefTitle> <RefYear>2024</RefYear> <RefBookTitle>Molecular Medical Microbiology</RefBookTitle> <RefPage>155-75</RefPage> <RefTotal>Li C, Ouyang Z, Liu J. Chapter 9 - Bacterial growth and cultivation. In: Tang YW, Hindiyeh MY, Liu D, Sails A, Spearman P, Zhang JR, editors. Molecular Medical Microbiology. Third Edition. Academic Press:2024. p. 155-75. DOI:10.1016/b978-0-12-818619-0.00070-8</RefTotal> <RefLink>https://doi.org/10.1016/b978-0-12-818619-0.00070-8</RefLink> </Reference> <Reference refNo="29"> <RefAuthor>Potera C</RefAuthor> <RefTitle>Antibiotic Candidate from Soil Hits Two Cell Wall Targets</RefTitle> <RefYear>2015</RefYear> <RefJournal>Microbe Magazine</RefJournal> <RefPage>138-9</RefPage> <RefTotal>Potera C. Antibiotic Candidate from Soil Hits Two Cell Wall Targets. Microbe Magazine. 2015 Apr 1 [cited 2024 Jun 8];10(4):138-9. DOI: 10.1128/microbe.10.138.1</RefTotal> <RefLink>https://doi.org/10.1128/microbe.10.138.1</RefLink> </Reference> <Reference refNo="30"> <RefAuthor>Krumberger M</RefAuthor> <RefAuthor>Li X</RefAuthor> <RefAuthor>Kreutzer AG</RefAuthor> <RefAuthor>Peoples AJ</RefAuthor> <RefAuthor>Nitti AG</RefAuthor> <RefAuthor>Cunningham AM</RefAuthor> <RefAuthor>Jones CR</RefAuthor> <RefAuthor>Achorn C</RefAuthor> <RefAuthor>Ling LL</RefAuthor> <RefAuthor>Hughes DE</RefAuthor> <RefAuthor>Nowick JS</RefAuthor> <RefTitle>Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29</RefTitle> <RefYear>2023</RefYear> <RefJournal>J Org Chem</RefJournal> <RefPage>2214-20</RefPage> <RefTotal>Krumberger M, Li X, Kreutzer AG, Peoples AJ, Nitti AG, Cunningham AM, Jones CR, Achorn C, Ling LL, Hughes DE, Nowick JS. Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29. J Org Chem. 2023 Feb;88(4):2214-20. DOI: 10.1021/acs.joc.2c02648</RefTotal> <RefLink>https://doi.org/10.1021/acs.joc.2c02648</RefLink> </Reference> <Reference refNo="31"> <RefAuthor>Vollmer W</RefAuthor> <RefTitle>Chapter 4 - Bacterial cell walls: peptidoglycan</RefTitle> <RefYear>2024</RefYear> <RefBookTitle>Molecular Medical Microbiology</RefBookTitle> <RefPage>45-67</RefPage> <RefTotal>Vollmer W. Chapter 4 - Bacterial cell walls: peptidoglycan. In: Tang YW, Hindiyeh MY, Liu D, Sails A, Spearman P, Zhang JR, editors. Molecular Medical Microbiology. Third Edition. Academic Press:2024. p. 45-67. DOI: 10.1016/b978-0-12-818619-0.00015-0</RefTotal> <RefLink>https://doi.org/10.1016/b978-0-12-818619-0.00015-0</RefLink> </Reference> <Reference refNo="32"> <RefAuthor>Ganesan N</RefAuthor> <RefAuthor>Mishra B</RefAuthor> <RefAuthor>Felix L</RefAuthor> <RefAuthor>Mylonakis E</RefAuthor> <RefTitle>Antimicrobial Peptides and Small Molecules Targeting the Cell Membrane of Staphylococcus aureus</RefTitle> <RefYear>2023</RefYear> <RefJournal>Microbiol Mol Biol Rev</RefJournal> <RefPage>e0003722</RefPage> <RefTotal>Ganesan N, Mishra B, Felix L, Mylonakis E. Antimicrobial Peptides and Small Molecules Targeting the Cell Membrane of Staphylococcus aureus. Microbiol Mol Biol Rev. 2023 Jun;87(2):e0003722. DOI: 10.1128/mmbr.00037-22</RefTotal> <RefLink>https://doi.org/10.1128/mmbr.00037-22</RefLink> </Reference> <Reference refNo="33"> <RefAuthor>Nikolic P</RefAuthor> <RefAuthor>Mudgil P</RefAuthor> <RefTitle>The Cell Wall, Cell Membrane and Virulence Factors of Staphylococcus aureus and Their Role in Antibiotic Resistance</RefTitle> <RefYear>2023</RefYear> <RefJournal>Microorganisms</RefJournal> <RefPage>259</RefPage> <RefTotal>Nikolic P, Mudgil P. The Cell Wall, Cell Membrane and Virulence Factors of Staphylococcus aureus and Their Role in Antibiotic Resistance. Microorganisms. 2023 Jan 19;11(2):259. DOI: 10.3390/microorganisms11020259</RefTotal> <RefLink>https://doi.org/10.3390/microorganisms11020259</RefLink> </Reference> <Reference refNo="34"> <RefAuthor>Zhang X</RefAuthor> <RefAuthor>Sun X</RefAuthor> <RefAuthor>Wu J</RefAuthor> <RefAuthor>Wu Y</RefAuthor> <RefAuthor>Wang Y</RefAuthor> <RefAuthor>Hu X</RefAuthor> <RefAuthor>Wang X</RefAuthor> <RefTitle>Berberine Damages the Cell Surface of Methicillin-Resistant</RefTitle> <RefYear>2020</RefYear> <RefJournal>Front Microbiol</RefJournal> <RefPage>621</RefPage> <RefTotal>Zhang X, Sun X, Wu J, Wu Y, Wang Y, Hu X, Wang X. Berberine Damages the Cell Surface of Methicillin-Resistant. Front Microbiol. 2020;11:621. DOI: 10.3389/fmicb.2020.00621</RefTotal> <RefLink>https://doi.org/10.3389/fmicb.2020.00621</RefLink> </Reference> <Reference refNo="35"> <RefAuthor>Giltrap AM</RefAuthor> <RefAuthor>Dowman LJ</RefAuthor> <RefAuthor>Nagalingam G</RefAuthor> <RefAuthor>Ochoa JL</RefAuthor> <RefAuthor>Linington RG</RefAuthor> <RefAuthor>Britton WJ</RefAuthor> <RefAuthor>Payne RJ</RefAuthor> <RefTitle>Total Synthesis of Teixobactin</RefTitle> <RefYear>2016</RefYear> <RefJournal>Org Lett</RefJournal> <RefPage>2788-91</RefPage> <RefTotal>Giltrap AM, Dowman LJ, Nagalingam G, Ochoa JL, Linington RG, Britton WJ, Payne RJ. Total Synthesis of Teixobactin. Org Lett. 2016 Jun;18(11):2788-91. DOI: 10.1021/acs.orglett.6b01324</RefTotal> <RefLink>https://doi.org/10.1021/acs.orglett.6b01324</RefLink> </Reference> <Reference refNo="36"> <RefAuthor>Shukla R</RefAuthor> <RefAuthor>Lavore F</RefAuthor> <RefAuthor>Maity S</RefAuthor> <RefAuthor>Derks MGN</RefAuthor> <RefAuthor>Jones CR</RefAuthor> <RefAuthor>Vermeulen BJA</RefAuthor> <RefAuthor>Melcrová A</RefAuthor> <RefAuthor>Morris MA</RefAuthor> <RefAuthor>Becker LM</RefAuthor> <RefAuthor>Wang X</RefAuthor> <RefAuthor>Kumar R</RefAuthor> <RefAuthor>Medeiros-Silva J</RefAuthor> <RefAuthor>van Beekveld RAM</RefAuthor> <RefAuthor>Bonvin AMJJ</RefAuthor> <RefAuthor>Lorent JH</RefAuthor> <RefAuthor>Lelli M</RefAuthor> <RefAuthor>Nowick JS</RefAuthor> <RefAuthor>MacGillavry HD</RefAuthor> <RefAuthor>Peoples AJ</RefAuthor> <RefAuthor>Spoering AL</RefAuthor> <RefAuthor>Ling LL</RefAuthor> <RefAuthor>Hughes DE</RefAuthor> <RefAuthor>Roos WH</RefAuthor> <RefAuthor>Breukink E</RefAuthor> <RefAuthor>Lewis K</RefAuthor> <RefAuthor>Weingarth M</RefAuthor> <RefTitle>Teixobactin kills bacteria by a two-pronged attack on the cell envelope</RefTitle> <RefYear>2022</RefYear> <RefJournal>Nature</RefJournal> <RefPage>390-6</RefPage> <RefTotal>Shukla R, Lavore F, Maity S, Derks MGN, Jones CR, Vermeulen BJA, Melcrová A, Morris MA, Becker LM, Wang X, Kumar R, Medeiros-Silva J, van Beekveld RAM, Bonvin AMJJ, Lorent JH, Lelli M, Nowick JS, MacGillavry HD, Peoples AJ, Spoering AL, Ling LL, Hughes DE, Roos WH, Breukink E, Lewis K, Weingarth M. Teixobactin kills bacteria by a two-pronged attack on the cell envelope. Nature. 2022 Aug;608(7922):390-6. DOI: 10.1038/s41586-022-05019-y</RefTotal> <RefLink>https://doi.org/10.1038/s41586-022-05019-y</RefLink> </Reference> <Reference refNo="37"> <RefAuthor>Zhang X</RefAuthor> <RefAuthor>Chen Y</RefAuthor> <RefAuthor>Yan T</RefAuthor> <RefAuthor>Wang H</RefAuthor> <RefAuthor>Zhang R</RefAuthor> <RefAuthor>Xu Y</RefAuthor> <RefAuthor>Hou Y</RefAuthor> <RefAuthor>Peng Q</RefAuthor> <RefAuthor>Song F</RefAuthor> <RefTitle>Cell death dependent on holins LrgAB repressed by a novel ArsR family regulator CdsR</RefTitle> <RefYear>2024</RefYear> <RefJournal>Cell Death Discov</RefJournal> <RefPage>173</RefPage> <RefTotal>Zhang X, Chen Y, Yan T, Wang H, Zhang R, Xu Y, Hou Y, Peng Q, Song F. Cell death dependent on holins LrgAB repressed by a novel ArsR family regulator CdsR. Cell Death Discov. 2024 Apr;10(1):173. DOI: 10.1038/s41420-024-01942-3</RefTotal> <RefLink>https://doi.org/10.1038/s41420-024-01942-3</RefLink> </Reference> <Reference refNo="38"> <RefAuthor>Dahyot S</RefAuthor> <RefAuthor>Oxaran V</RefAuthor> <RefAuthor>Niepceron M</RefAuthor> <RefAuthor>Dupart E</RefAuthor> <RefAuthor>Legris S</RefAuthor> <RefAuthor>Destruel L</RefAuthor> <RefAuthor>Didi J</RefAuthor> <RefAuthor>Clamens T</RefAuthor> <RefAuthor>Lesouhaitier O</RefAuthor> <RefAuthor>Zerdoumi Y</RefAuthor> <RefAuthor>Flaman JM</RefAuthor> <RefAuthor>Pestel-Caron M</RefAuthor> <RefTitle>Role of the LytSR Two-Component Regulatory System in Biofilm Formation and Pathogenesis</RefTitle> <RefYear>2020</RefYear> <RefJournal>Front Microbiol</RefJournal> <RefPage>39</RefPage> <RefTotal>Dahyot S, Oxaran V, Niepceron M, Dupart E, Legris S, Destruel L, Didi J, Clamens T, Lesouhaitier O, Zerdoumi Y, Flaman JM, Pestel-Caron M. Role of the LytSR Two-Component Regulatory System in Biofilm Formation and Pathogenesis. Front Microbiol. 2020;11:39. DOI: 10.3389/fmicb.2020.00039</RefTotal> <RefLink>https://doi.org/10.3389/fmicb.2020.00039</RefLink> </Reference> <Reference refNo="39"> <RefAuthor>Sarkar P</RefAuthor> <RefAuthor>Yarlagadda V</RefAuthor> <RefAuthor>Ghosh C</RefAuthor> <RefAuthor>Haldar J</RefAuthor> <RefTitle>A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics</RefTitle> <RefYear>2017</RefYear> <RefJournal>Medchemcomm</RefJournal> <RefPage>516-33</RefPage> <RefTotal>Sarkar P, Yarlagadda V, Ghosh C, Haldar J. A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics. Medchemcomm. 2017 Mar;8(3):516-33. DOI: 10.1039/c6md00585c</RefTotal> <RefLink>https://doi.org/10.1039/c6md00585c</RefLink> </Reference> <Reference refNo="40"> <RefAuthor>Hussein M</RefAuthor> <RefAuthor>Karas JA</RefAuthor> <RefAuthor>Schneider-Futschik EK</RefAuthor> <RefAuthor>Chen F</RefAuthor> <RefAuthor>Swarbrick J</RefAuthor> <RefAuthor>Paulin OKA</RefAuthor> <RefAuthor>Hoyer D</RefAuthor> <RefAuthor>Baker M</RefAuthor> <RefAuthor>Zhu Y</RefAuthor> <RefAuthor>Li J</RefAuthor> <RefAuthor>Velkov T</RefAuthor> <RefTitle>The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study</RefTitle> <RefYear>2020</RefYear> <RefJournal>mSystems</RefJournal> <RefPage>e00077-20</RefPage> <RefTotal>Hussein M, Karas JA, Schneider-Futschik EK, Chen F, Swarbrick J, Paulin OKA, Hoyer D, Baker M, Zhu Y, Li J, Velkov T. The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study. mSystems. 2020 May 26;5(3):e00077-20. DOI: 10.1128/mSystems.00077-20</RefTotal> <RefLink>https://doi.org/10.1128/mSystems.00077-20</RefLink> </Reference> <Reference refNo="41"> <RefAuthor>Baran A</RefAuthor> <RefAuthor>Kwiatkowska A</RefAuthor> <RefAuthor>Potocki L</RefAuthor> <RefTitle>Antibiotics and Bacterial Resistance-A Short Story of an Endless Arms Race</RefTitle> <RefYear>2023</RefYear> <RefJournal>Int J Mol Sci</RefJournal> <RefPage>5777</RefPage> <RefTotal>Baran A, Kwiatkowska A, Potocki L. Antibiotics and Bacterial Resistance-A Short Story of an Endless Arms Race. Int J Mol Sci. 2023 Mar;24(6):5777. DOI: 10.3390/ijms24065777</RefTotal> <RefLink>https://doi.org/10.3390/ijms24065777</RefLink> </Reference> <Reference refNo="42"> <RefAuthor>Li X</RefAuthor> <RefAuthor>Wu M</RefAuthor> <RefAuthor>Shuai J</RefAuthor> <RefTitle>Clovibactin: A revolutionary antibiotic unleashing lethal efficacy against pathogens with little drug resistance</RefTitle> <RefYear>2024</RefYear> <RefJournal>Sci Bull (Beijing)</RefJournal> <RefPage>570-3</RefPage> <RefTotal>Li X, Wu M, Shuai J. Clovibactin: A revolutionary antibiotic unleashing lethal efficacy against pathogens with little drug resistance. Sci Bull (Beijing). 2024 Mar;69(5):570-3. DOI: 10.1016/j.scib.2023.12.047</RefTotal> <RefLink>https://doi.org/10.1016/j.scib.2023.12.047</RefLink> </Reference> <Reference refNo="43"> <RefAuthor>Silver LL</RefAuthor> <RefTitle>Multi-targeting by monotherapeutic antibacterials</RefTitle> <RefYear>2007</RefYear> <RefJournal>Nat Rev Drug Discov</RefJournal> <RefPage>41-55</RefPage> <RefTotal>Silver LL. Multi-targeting by monotherapeutic antibacterials. Nat Rev Drug Discov. 2007 Jan;6(1):41-55. DOI: 10.1038/nrd2202</RefTotal> <RefLink>https://doi.org/10.1038/nrd2202</RefLink> </Reference> <Reference refNo="44"> <RefAuthor>Huang S</RefAuthor> <RefAuthor>Huang J</RefAuthor> <RefAuthor>Du J</RefAuthor> <RefAuthor>Li Y</RefAuthor> <RefAuthor>Wu M</RefAuthor> <RefAuthor>Chen S</RefAuthor> <RefAuthor>Zhan L</RefAuthor> <RefAuthor>Huang X</RefAuthor> <RefTitle>The LiaSR Two-Component System Regulates Resistance to Chlorhexidine in Streptococcus mutans</RefTitle> <RefYear>2024</RefYear> <RefJournal>Microorganisms</RefJournal> <RefPage>468</RefPage> <RefTotal>Huang S, Huang J, Du J, Li Y, Wu M, Chen S, Zhan L, Huang X. The LiaSR Two-Component System Regulates Resistance to Chlorhexidine in Streptococcus mutans. Microorganisms. 2024 Feb 26;12(3):468. DOI: 10.3390/microorganisms12030468</RefTotal> <RefLink>https://doi.org/10.3390/microorganisms12030468</RefLink> </Reference> <Reference refNo="45"> <RefAuthor>Kobras CM</RefAuthor> <RefAuthor>Mascher T</RefAuthor> <RefAuthor>Gebhard S</RefAuthor> <RefTitle>Application of a Bacillus subtilis Whole-Cell Biosensor (PliaI-lux) for the Identification of Cell Wall Active Antibacterial Compounds</RefTitle> <RefYear>2017</RefYear> <RefJournal>Methods Mol Biol</RefJournal> <RefPage>121-31</RefPage> <RefTotal>Kobras CM, Mascher T, Gebhard S. Application of a Bacillus subtilis Whole-Cell Biosensor (PliaI-lux) for the Identification of Cell Wall Active Antibacterial Compounds. Methods Mol Biol. 2017;1520:121-31. DOI: 10.1007/978-1-4939-6634-9_7</RefTotal> <RefLink>https://doi.org/10.1007/978-1-4939-6634-9_7</RefLink> </Reference> <Reference refNo="46"> <RefAuthor>Sipahi OR</RefAuthor> <RefTitle>Economics of antibiotic resistance</RefTitle> <RefYear>2008</RefYear> <RefJournal>Expert Rev Anti Infect Ther</RefJournal> <RefPage>523-39</RefPage> <RefTotal>Sipahi OR. Economics of antibiotic resistance. Expert Rev Anti Infect Ther. 2008 Aug;6(4):523-39. DOI: 10.1586/14787210.6.4.523</RefTotal> <RefLink>https://doi.org/10.1586/14787210.6.4.523</RefLink> </Reference> <Reference refNo="47"> <RefAuthor>Appelbaum PC</RefAuthor> <RefTitle>Reduced glycopeptide susceptibility in methicillin-resistant Staphylococcus aureus (MRSA)</RefTitle> <RefYear>2007</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>398-408</RefPage> <RefTotal>Appelbaum PC. Reduced glycopeptide susceptibility in methicillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents. 2007 Nov;30(5):398-408. DOI: 10.1016/j.ijantimicag.2007.07.011</RefTotal> <RefLink>https://doi.org/10.1016/j.ijantimicag.2007.07.011</RefLink> </Reference> <Reference refNo="48"> <RefAuthor>Yang R</RefAuthor> <RefAuthor>Cheng W</RefAuthor> <RefAuthor>Huang M</RefAuthor> <RefAuthor>Xu T</RefAuthor> <RefAuthor>Zhang M</RefAuthor> <RefAuthor>Liu J</RefAuthor> <RefAuthor>Qin S</RefAuthor> <RefAuthor>Guo Y</RefAuthor> <RefTitle>Novel membrane-targeting isoxanthohumol-amine conjugates for combating methicillin-resistant Staphylococcus aureus (MRSA) infections</RefTitle> <RefYear>2024</RefYear> <RefJournal>Eur J Med Chem</RefJournal> <RefPage>116274</RefPage> <RefTotal>Yang R, Cheng W, Huang M, Xu T, Zhang M, Liu J, Qin S, Guo Y. Novel membrane-targeting isoxanthohumol-amine conjugates for combating methicillin-resistant Staphylococcus aureus (MRSA) infections. Eur J Med Chem. 2024 Mar;268:116274. DOI: 10.1016/j.ejmech.2024.116274</RefTotal> <RefLink>https://doi.org/10.1016/j.ejmech.2024.116274</RefLink> </Reference> <Reference refNo="49"> <RefAuthor>Fazili T</RefAuthor> <RefAuthor>Bansal E</RefAuthor> <RefAuthor>Garner D</RefAuthor> <RefAuthor>Gomez M</RefAuthor> <RefAuthor>Stornelli N</RefAuthor> <RefTitle>Dalbavancin as sequential therapy for infective endocarditis due to Gram-positive organisms: a review</RefTitle> <RefYear>2023</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>106749</RefPage> <RefTotal>Fazili T, Bansal E, Garner D, Gomez M, Stornelli N. Dalbavancin as sequential therapy for infective endocarditis due to Gram-positive organisms: a review. Int J Antimicrob Agents. 2023 Apr;61(4):106749. DOI: 10.1016/j.ijantimicag.2023.106749</RefTotal> <RefLink>https://doi.org/10.1016/j.ijantimicag.2023.106749</RefLink> </Reference> <Reference refNo="50"> <RefAuthor>Piddock LJ</RefAuthor> <RefTitle>Teixobactin, the first of a new class of antibiotics discovered by iChip technology?</RefTitle> <RefYear>2015</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>2679-80</RefPage> <RefTotal>Piddock LJ. Teixobactin, the first of a new class of antibiotics discovered by iChip technology? J Antimicrob Chemother. 2015 Oct;70(10):2679-80. DOI: 10.1093/jac/dkv175</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkv175</RefLink> </Reference> </References> <Media> <Tables> <NoOfTables>0</NoOfTables> </Tables> <Figures> <Figure format="png" height="570" width="690"> <MediaNo>1</MediaNo> <MediaID>1</MediaID> <Caption><Pgraph><Mark1>Figure 1: Three-dimensional structure of clovibactin, teixobactin, kalimantacin and vancomycin</Mark1></Pgraph></Caption> </Figure> <Figure format="png" height="484" width="960"> <MediaNo>2</MediaNo> <MediaID>2</MediaID> <Caption><Pgraph><Mark1>Figure 2: Cultivation of bacteria using the iChip device</Mark1></Pgraph></Caption> </Figure> <Figure format="png" height="486" width="688"> <MediaNo>3</MediaNo> <MediaID>3</MediaID> <Caption><Pgraph><Mark1>Figure 3: Mechanism of action. Diagrams show how clovibactin interacts with the peptidoglycan layer of </Mark1><Mark1><Mark2>S. aureus</Mark2></Mark1><Mark1> and inhibits cell wall synthesis.</Mark1></Pgraph></Caption> </Figure> <Figure format="png" height="1146" width="880"> <MediaNo>4</MediaNo> <MediaID>4</MediaID> <Caption><Pgraph><Mark1>Figure 4: Current and future hot spot in clovibactin research</Mark1></Pgraph></Caption> </Figure> <NoOfPictures>4</NoOfPictures> </Figures> <InlineFigures> <NoOfPictures>0</NoOfPictures> </InlineFigures> <Attachments> <NoOfAttachments>0</NoOfAttachments> </Attachments> </Media> </OrigData> </GmsArticle>