{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:02:52Z","timestamp":1790683372528,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011536","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T00:00:00Z","timestamp":1691020800000}}],"reference-count":99,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:00:00Z","timestamp":1690156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001590","name":"Health Research Board","doi-asserted-by":"publisher","award":["ILP-POR-2019-102"],"award-info":[{"award-number":["ILP-POR-2019-102"]}],"id":[{"id":"10.13039\/501100001590","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001590","name":"Health Research Board","doi-asserted-by":"publisher","award":["HRA-POR-2015-1158"],"award-info":[{"award-number":["HRA-POR-2015-1158"]}],"id":[{"id":"10.13039\/501100001590","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["19\/FFP\/6441"],"award-info":[{"award-number":["19\/FFP\/6441"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001596","name":"Irish Research Council for Science, Engineering and Technology","doi-asserted-by":"publisher","award":["GOIPG\/2019\/2011"],"award-info":[{"award-number":["GOIPG\/2019\/2011"]}],"id":[{"id":"10.13039\/501100001596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI083211"],"award-info":[{"award-number":["P01 AI083211"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI125588"],"award-info":[{"award-number":["R01 AI125588"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The laboratory for molecular infection Medicine Sweden"},{"name":"the Knut and Alice Wallenberg Foundation"},{"DOI":"10.13039\/100016756","name":"the Kempe Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016756","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In <jats:italic>Staphylococcus aureus<\/jats:italic> the role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase gene <jats:italic>pgl<\/jats:italic>, which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to \u03b2-lactam antibiotics, particularly in chemically defined media with physiologically-relevant concentrations of glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in the <jats:italic>pgl<\/jats:italic> mutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased \u03b2-lactam resistance. Morphologically, <jats:italic>pgl<\/jats:italic> mutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. The <jats:italic>pgl<\/jats:italic> mutation reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Levels of lipoteichoic acids (LTAs) were significantly reduced in <jats:italic>pgl<\/jats:italic>, which may limit cell lysis, while the surface charge of <jats:italic>pgl<\/jats:italic> cells was significantly more positive. A <jats:italic>vraG<\/jats:italic> mutation in <jats:italic>pgl<\/jats:italic> reversed the increased OX resistance phenotype, and partially restored wild-type surface charge, but not LTA levels. Mutations in <jats:italic>vraF<\/jats:italic> or <jats:italic>graRS<\/jats:italic> from the VraFG\/GraRS complex that regulates DltABCD-mediated <jats:sc>d<\/jats:sc>-alanylation of teichoic acids (which in turn controls \u03b2-lactam resistance and surface charge), also restored wild-type OX susceptibility. Collectively these data show that reduced levels of LTAs and OX-induced lysis combined with a VraFG\/GraRS-dependent increase in cell surface positive charge are accompanied by significantly increased OX resistance in an MRSA <jats:italic>pgl<\/jats:italic> mutant.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011536","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T17:27:37Z","timestamp":1690219657000},"page":"e1011536","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":38,"title":["Metabolic reprogramming and altered cell envelope characteristics in a pentose phosphate pathway mutant increases MRSA resistance to \u03b2-lactam antibiotics"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3636-700X","authenticated-orcid":true,"given":"Merve S.","family":"Zeden","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Bueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron C.","family":"Nolan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongsam","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhananjay","family":"Shinde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fareha","family":"Razvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Sladek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d3rla","family":"Burke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eoghan","family":"O\u2019Neill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Fey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Cava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinai C.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3866-7161","authenticated-orcid":true,"given":"James P.","family":"O\u2019Gara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,7,24]]},"reference":[{"issue":"5","key":"ppat.1011536.ref001","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1093\/jac\/dkac028","article-title":"Global consumption of antimicrobials: impact of the WHO Global Action Plan on Antimicrobial Resistance and 2019 coronavirus pandemic (COVID-19).","volume":"77","author":"T Khouja","year":"2022","journal-title":"J Antimicrob Chemother"},{"issue":"5","key":"ppat.1011536.ref002","doi-asserted-by":"crossref","first-page":"325","DOI":"10.7196\/SAMJ.9644","article-title":"The World Health Organization Global Action Plan for antimicrobial resistance","volume":"105","author":"M Mendelson","year":"2015","journal-title":"S Afr Med J"},{"issue":"8","key":"ppat.1011536.ref003","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJM199808203390806","article-title":"Staphylococcus aureus infections","volume":"339","author":"FD Lowy","year":"1998","journal-title":"N Engl J Med"},{"issue":"3","key":"ppat.1011536.ref004","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1128\/CMR.10.3.505","article-title":"Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks","volume":"10","author":"J Kluytmans","year":"1997","journal-title":"Clin Microbiol Rev"},{"issue":"6","key":"ppat.1011536.ref005","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1006\/mpat.1999.0272","article-title":"Mechanisms of Staphylococcus aureus invasion of cultured osteoblasts","volume":"26","author":"JK Ellington","year":"1999","journal-title":"Microb Pathog"},{"issue":"1","key":"ppat.1011536.ref006","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1053\/jinf.2000.0657","article-title":"Clinical isolates of Staphylococcus aureus exhibit diversity in fnb genes and adhesion to human fibronectin.","volume":"41","author":"SJ Peacock","year":"2000","journal-title":"J Infection"},{"issue":"12","key":"ppat.1011536.ref007","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S0966-842X(98)01400-0","article-title":"Surface protein adhesins of Staphylococcus aureus","volume":"6","author":"TJ Foster","year":"1998","journal-title":"Trends in Microbiology"},{"issue":"3","key":"ppat.1011536.ref008","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1128\/CMR.00134-14","article-title":"Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management","volume":"28","author":"SY Tong","year":"2015","journal-title":"Clin Microbiol Rev"},{"issue":"12","key":"ppat.1011536.ref009","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/S1473-3099(05)70295-4","article-title":"The role of nasal carriage in Staphylococcus aureus infections","volume":"5","author":"HF Wertheim","year":"2005","journal-title":"Lancet Infect Dis"},{"key":"ppat.1011536.ref010","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1099\/00221287-145-12-3477","article-title":"Bacterial fibronectin-binding proteins and endothelial cell surface fibronectin mediate adherence of Staphylococcus aureus to resting human endothelial cells","volume":"145","author":"SJ Peacock","year":"1999","journal-title":"Microbiol-Uk"},{"issue":"6","key":"ppat.1011536.ref011","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1086\/314762","article-title":"Characterization of the relationship between polysaccharide intercellular adhesin and hemagglutination in Staphylococcus epidermidis","volume":"179","author":"PD Fey","year":"1999","journal-title":"J Infect Dis"},{"issue":"3","key":"ppat.1011536.ref012","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1093\/infdis\/144.3.237","article-title":"Efficacy of ampicillin plus a beta-lactamase inhibitor (CP-45,899) in experimental endocarditis due to Staphylococcus aureus.","volume":"144","author":"RG Washburn","year":"1981","journal-title":"J Infect Dis"},{"issue":"2","key":"ppat.1011536.ref013","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1046\/j.1365-2958.1999.01353.x","article-title":"A novel mechanism of phase variation of virulence in Staphylococcus epidermidis: evidence for control of the polysaccharide intercellular adhesin synthesis by alternating insertion and excision of the insertion sequence element IS256","volume":"32","author":"W Ziebuhr","year":"1999","journal-title":"Molecular Microbiology"},{"issue":"4534","key":"ppat.1011536.ref014","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1136\/bmj.2.4534.863","article-title":"Staphylococcal infection due to penicillin-resistant strains","volume":"2","author":"M. Barber","year":"1947","journal-title":"Br Med J"},{"issue":"5","key":"ppat.1011536.ref015","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1128\/AAC.37.5.1144","article-title":"blaI and blaR1 regulate beta-lactamase and PBP 2a production in methicillin-resistant Staphylococcus aureus","volume":"37","author":"CJ Hackbarth","year":"1993","journal-title":"Antimicrob Agents Chemother"},{"key":"ppat.1011536.ref016","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1136\/jcp.14.4.385","article-title":"Methicillin-resistant staphylococci","volume":"14","author":"M. Barber","year":"1961","journal-title":"J Clin Pathol"},{"issue":"18","key":"ppat.1011536.ref017","doi-asserted-by":"crossref","first-page":"5548","DOI":"10.1093\/nar\/18.18.5548","article-title":"Complete nucleotide sequence of IS431mec in Staphylococcus aureus","volume":"18","author":"L Barberis-Maino","year":"1990","journal-title":"Nucleic Acids Res"},{"issue":"1\u20132","key":"ppat.1011536.ref018","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/BF00261186","article-title":"FemA, a host-mediated factor essential for methicillin resistance in Staphylococcus aureus: molecular cloning and characterization","volume":"219","author":"B Berger-Bachi","year":"1989","journal-title":"Mol Gen Genet"},{"issue":"1","key":"ppat.1011536.ref019","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/0378-1119(90)90481-6","article-title":"Sequence comparison of mecA genes isolated from methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis","volume":"94","author":"C Ryffel","year":"1990","journal-title":"Gene"},{"issue":"19","key":"ppat.1011536.ref020","doi-asserted-by":"crossref","first-page":"10886","DOI":"10.1073\/pnas.191260798","article-title":"An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci","volume":"98","author":"MG Pinho","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"22","key":"ppat.1011536.ref021","doi-asserted-by":"crossref","first-page":"6525","DOI":"10.1128\/JB.183.22.6525-6531.2001","article-title":"Complementation of the essential peptidoglycan transpeptidase function of penicillin-binding protein 2 (PBP2) by the drug resistance protein PBP2A in Staphylococcus aureus.","volume":"183","author":"MG Pinho","year":"2001","journal-title":"J Bacteriol"},{"issue":"8","key":"ppat.1011536.ref022","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1128\/AAC.02802-14","article-title":"beta-Lactam resistance in methicillin-resistant Staphylococcus aureus USA300 is increased by inactivation of the ClpXP protease","volume":"58","author":"KT Baek","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"issue":"7","key":"ppat.1011536.ref023","doi-asserted-by":"crossref","first-page":"e1008672","DOI":"10.1371\/journal.ppat.1008672","article-title":"Evolving MRSA: High-level beta-lactam resistance in Staphylococcus aureus is associated with RNA Polymerase alterations and fine tuning of gene expression","volume":"16","author":"VV Panchal","year":"2020","journal-title":"PLoS Pathog"},{"issue":"12","key":"ppat.1011536.ref024","doi-asserted-by":"crossref","first-page":"e82814","DOI":"10.1371\/journal.pone.0082814","article-title":"The mechanism of heterogeneous beta-lactam resistance in MRSA: key role of the stringent stress response.","volume":"8","author":"C Kim","year":"2013","journal-title":"PLoS One"},{"key":"ppat.1011536.ref025","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1146\/annurev-biochem-060614-034516","article-title":"Mechanisms of Methicillin Resistance in Staphylococcus aureus","volume":"84","author":"SJ Peacock","year":"2015","journal-title":"Annu Rev Biochem"},{"issue":"2","key":"ppat.1011536.ref026","doi-asserted-by":"crossref","first-page":"e01000","DOI":"10.1128\/mBio.01000-13","article-title":"Novel determinants of antibiotic resistance: identification of mutated loci in highly methicillin-resistant subpopulations of methicillin-resistant Staphylococcus aureus.","volume":"5","author":"J Dordel","year":"2014","journal-title":"MBio"},{"key":"ppat.1011536.ref027","doi-asserted-by":"crossref","first-page":"106283","DOI":"10.1016\/j.ijantimicag.2021.106283","article-title":"The Novel Membrane-Associated Auxiliary Factors AuxA and AuxB Modulate beta-lactam Resistance in MRSA by stabilizing Lipoteichoic Acids.","author":"K Mikkelsen","year":"2021","journal-title":"Int J Antimicrob Agents."},{"issue":"2","key":"ppat.1011536.ref028","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1089\/mdr.1996.2.277","article-title":"A phosphoglucomutase-like gene essential for the optimal expression of methicillin resistance in Staphylococcus aureus: molecular cloning and DNA sequencing","volume":"2","author":"S Wu","year":"1996","journal-title":"Microb Drug Resist"},{"issue":"6","key":"ppat.1011536.ref029","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1128\/JB.186.6.1705-1713.2004","article-title":"Role of murE in the Expression of beta-lactam antibiotic resistance in Staphylococcus aureus","volume":"186","author":"S Gardete","year":"2004","journal-title":"J Bacteriol"},{"issue":"4","key":"ppat.1011536.ref030","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1128\/AAC.02697-15","article-title":"Role of the Stringent Stress Response in the Antibiotic Resistance Phenotype of Methicillin-Resistant Staphylococcus aureus","volume":"60","author":"S Aedo","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"ppat.1011536.ref031","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01931-19","article-title":"The Sle1 Cell Wall Amidase Is Essential for beta-Lactam Resistance in Community-Acquired Methicillin-Resistant Staphylococcus aureus USA300","volume":"64","author":"I Thalso-Madsen","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"ppat.1011536.ref032","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1128\/AAC.02333-15","article-title":"The Staphylococcus aureus Chaperone PrsA Is a New Auxiliary Factor of Oxacillin Resistance Affecting Penicillin-Binding Protein 2A","volume":"60","author":"A Jousselin","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"issue":"11","key":"ppat.1011536.ref033","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1128\/AAC.00049-08","article-title":"Staphylococcus aureus PBP4 is essential for beta-lactam resistance in community-acquired methicillin-resistant strains","volume":"52","author":"G Memmi","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"ppat.1011536.ref034","doi-asserted-by":"crossref","DOI":"10.1128\/JB.00574-18","article-title":"Inactivation of the Monofunctional Peptidoglycan Glycosyltransferase SgtB Allows Staphylococcus aureus To Survive in the Absence of Lipoteichoic Acid","volume":"201","author":"E Karinou","year":"2019","journal-title":"J Bacteriol"},{"issue":"9","key":"ppat.1011536.ref035","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/bi4016742","article-title":"Cross-link formation and peptidoglycan lattice assembly in the FemA mutant of Staphylococcus aureus","volume":"53","author":"SJ Kim","year":"2014","journal-title":"Biochemistry"},{"issue":"2","key":"ppat.1011536.ref036","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/j.1365-2958.2009.06648.x","article-title":"The nature of Staphylococcus aureus MurA and MurZ and approaches for detection of peptidoglycan biosynthesis inhibitors","volume":"72","author":"KL Blake","year":"2009","journal-title":"Mol Microbiol"},{"issue":"22","key":"ppat.1011536.ref037","doi-asserted-by":"crossref","first-page":"12394","DOI":"10.1073\/pnas.1922211117","article-title":"Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection","volume":"117","author":"AD Potter","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1011536.ref038","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01434-16","article-title":"Amino Acid Catabolism in Staphylococcus aureus and the Function of Carbon Catabolite Repression.","volume":"8","author":"CR Halsey","year":"2017","journal-title":"mBio"},{"issue":"3","key":"ppat.1011536.ref039","doi-asserted-by":"crossref","first-page":"e0053021","DOI":"10.1128\/mBio.00530-21","article-title":"Accumulation of Succinyl Coenzyme A Perturbs the Methicillin-Resistant Staphylococcus aureus (MRSA) Succinylome and Is Associated with Increased Susceptibility to Beta-Lactam Antibiotics.","volume":"12","author":"C Campbell","year":"2021","journal-title":"mBio"},{"issue":"11","key":"ppat.1011536.ref040","doi-asserted-by":"crossref","first-page":"e1003033","DOI":"10.1371\/journal.ppat.1003033","article-title":"CcpA regulates arginine biosynthesis in Staphylococcus aureus through repression of proline catabolism.","volume":"8","author":"AS Nuxoll","year":"2012","journal-title":"PLoS Pathog"},{"issue":"9","key":"ppat.1011536.ref041","doi-asserted-by":"crossref","first-page":"e1002217","DOI":"10.1371\/journal.ppat.1002217","article-title":"c-di-AMP is a new second messenger in Staphylococcus aureus with a role in controlling cell size and envelope stress","volume":"7","author":"RM Corrigan","year":"2011","journal-title":"PLoS Pathog"},{"issue":"2","key":"ppat.1011536.ref042","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1128\/MMBR.00005-09","article-title":"At the crossroads of bacterial metabolism and virulence factor synthesis in Staphylococci","volume":"73","author":"GA Somerville","year":"2009","journal-title":"Microbiol Mol Biol Rev"},{"issue":"1","key":"ppat.1011536.ref043","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02272-17","article-title":"Staphylococcus aureus Responds to the Central Metabolite Pyruvate To Regulate Virulence.","volume":"9","author":"L Harper","year":"2018","journal-title":"mBio"},{"issue":"3","key":"ppat.1011536.ref044","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00296-16","article-title":"Expanded Glucose Import Capability Affords Staphylococcus aureus Optimized Glycolytic Flux during Infection.","volume":"7","author":"NP Vitko","year":"2016","journal-title":"mBio"},{"issue":"2","key":"ppat.1011536.ref045","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00045-15","article-title":"Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus","volume":"6","author":"NP Vitko","year":"2015","journal-title":"mBio"},{"issue":"12","key":"ppat.1011536.ref046","doi-asserted-by":"crossref","first-page":"5223","DOI":"10.1128\/IAI.00762-10","article-title":"Comparison of the regulation, metabolic functions, and roles in virulence of the glyceraldehyde-3-phosphate dehydrogenase homologues gapA and gapB in Staphylococcus aureus","volume":"78","author":"J Purves","year":"2010","journal-title":"Infect Immun"},{"issue":"3","key":"ppat.1011536.ref047","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1111\/brv.12140","article-title":"The return of metabolism: biochemistry and physiology of the pentose phosphate pathway","volume":"90","author":"A Stincone","year":"2015","journal-title":"Biol Rev Camb Philos Soc"},{"issue":"12","key":"ppat.1011536.ref048","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1093\/infdis\/jiz404","article-title":"Transketolase of Staphylococcus aureus in the Control of Master Regulators of Stress Response During Infection","volume":"220","author":"X Tan","year":"2019","journal-title":"J Infect Dis"},{"issue":"1","key":"ppat.1011536.ref049","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01608-17","article-title":"Metabolic Mitigation of Staphylococcus aureus Vancomycin Intermediate-Level Susceptibility","volume":"62","author":"SG Gardner","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"issue":"11","key":"ppat.1011536.ref050","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00452-17","article-title":"Prevalence of Slow-Growth Vancomycin Nonsusceptibility in Methicillin-Resistant Staphylococcus aureus","volume":"61","author":"Y Katayama","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"issue":"27","key":"ppat.1011536.ref051","doi-asserted-by":"crossref","first-page":"13563","DOI":"10.1073\/pnas.1904280116","article-title":"The purine biosynthesis regulator PurR moonlights as a virulence regulator in Staphylococcus aureus","volume":"116","author":"WE Sause","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1011536.ref052","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/s41467-019-08724-x","article-title":"Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence.","volume":"10","author":"MI Goncheva","year":"2019","journal-title":"Nat Commun"},{"key":"ppat.1011536.ref053","first-page":"e0247822","article-title":"Purine Nucleosides Interfere with c-di-AMP Levels and Act as Adjuvants To Re-Sensitize MRSA To beta-Lactam Antibiotics.","author":"AC Nolan","year":"2022","journal-title":"mBio"},{"issue":"9","key":"ppat.1011536.ref054","doi-asserted-by":"crossref","first-page":"3180","DOI":"10.1074\/jbc.M117.818716","article-title":"Cyclic di-adenosine monophosphate (c-di-AMP) is required for osmotic regulation in Staphylococcus aureus but dispensable for viability in anaerobic conditions.","volume":"293","author":"MS Zeden","year":"2018","journal-title":"J Biol Chem"},{"key":"ppat.1011536.ref055","doi-asserted-by":"crossref","first-page":"339","DOI":"10.3389\/fmicb.2019.00339","article-title":"RelQ Mediates the Expression of beta-Lactam Resistance in Methicillin-Resistant Staphylococcus aureus.","volume":"10","author":"A Bhawini","year":"2019","journal-title":"Front Microbiol."},{"issue":"4","key":"ppat.1011536.ref056","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1128\/JB.01201-13","article-title":"Two small (p)ppGpp synthases in Staphylococcus aureus mediate tolerance against cell envelope stress conditions.","volume":"196","author":"T Geiger","year":"2014","journal-title":"J Bacteriol"},{"issue":"1","key":"ppat.1011536.ref057","first-page":"e00537","article-title":"A genetic resource for rapid and comprehensive phenotype screening of nonessential Staphylococcus aureus genes.","volume":"4","author":"PD Fey","year":"2013","journal-title":"MBio"},{"issue":"7","key":"ppat.1011536.ref058","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.1128\/IAI.01511-08","article-title":"Listeria monocytogenes 6-Phosphogluconolactonase mutants induce increased activation of a host cytosolic surveillance pathway","volume":"77","author":"GT Crimmins","year":"2009","journal-title":"Infect Immun"},{"issue":"44","key":"ppat.1011536.ref059","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2106022118","article-title":"Demonstration of the role of cell wall homeostasis in Staphylococcus aureus growth and the action of bactericidal antibiotics","volume":"118","author":"B Salamaga","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"Suppl A","key":"ppat.1011536.ref060","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/jac\/15.suppl_A.15","article-title":"Low concentrations of antibiotics","volume":"15","author":"V. Lorian","year":"1985","journal-title":"J Antimicrob Chemother"},{"issue":"3","key":"ppat.1011536.ref061","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1046\/j.1365-2958.2003.03719.x","article-title":"Dispersed mode of Staphylococcus aureus cell wall synthesis in the absence of the division machinery","volume":"50","author":"MG Pinho","year":"2003","journal-title":"Mol Microbiol"},{"issue":"6","key":"ppat.1011536.ref062","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1016\/S0021-9258(19)45556-7","article-title":"Glucose metabolism in 6 phosphogluconolactonase mutants of Escherichia coli","volume":"247","author":"SR Kupor","year":"1972","journal-title":"J Biol Chem"},{"issue":"1","key":"ppat.1011536.ref063","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1093\/infdis\/jiw461","article-title":"Redeploying beta-lactam antibiotics as a novel antivirulence strategy for the treatment of methicillin-resistant Staphylococcus aureus infections","volume":"215","author":"EM Waters","year":"2017","journal-title":"J Infect Dis"},{"issue":"4","key":"ppat.1011536.ref064","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-018-0060-y","article-title":"A guide to (13)C metabolic flux analysis for the cancer biologist.","volume":"50","author":"MR Antoniewicz","year":"2018","journal-title":"Exp Mol Med"},{"issue":"1","key":"ppat.1011536.ref065","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1021\/cb100269f","article-title":"Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus","volume":"6","author":"J Campbell","year":"2011","journal-title":"ACS Chem Biol"},{"issue":"4","key":"ppat.1011536.ref066","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00950-16","article-title":"Multidrug Intrinsic Resistance Factors in Staphylococcus aureus Identified by Profiling Fitness within High-Diversity Transposon Libraries.","volume":"7","author":"M Rajagopal","year":"2016","journal-title":"mBio"},{"issue":"13","key":"ppat.1011536.ref067","doi-asserted-by":"crossref","first-page":"8405","DOI":"10.1074\/jbc.274.13.8405","article-title":"Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides","volume":"274","author":"A Peschel","year":"1999","journal-title":"J Biol Chem"},{"issue":"3","key":"ppat.1011536.ref068","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1021\/jacs.7b11704","article-title":"Reconstitution of Staphylococcus aureus Lipoteichoic Acid Synthase Activity Identifies Congo Red as a Selective Inhibitor","volume":"140","author":"CR Vickery","year":"2018","journal-title":"J Am Chem Soc"},{"issue":"5","key":"ppat.1011536.ref069","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1111\/j.1365-2958.2007.05986.x","article-title":"The antimicrobial peptide-sensing system aps of Staphylococcus aureus","volume":"66","author":"M Li","year":"2007","journal-title":"Mol Microbiol"},{"issue":"22","key":"ppat.1011536.ref070","doi-asserted-by":"crossref","first-page":"9469","DOI":"10.1073\/pnas.0702159104","article-title":"Gram-positive three-component antimicrobial peptide-sensing system","volume":"104","author":"M Li","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"ppat.1011536.ref071","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1128\/AAC.00209-07","article-title":"Interaction of the GraRS two-component system with the VraFG ABC transporter to support vancomycin-intermediate resistance in Staphylococcus aureus","volume":"51","author":"M Meehl","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"issue":"7","key":"ppat.1011536.ref072","doi-asserted-by":"crossref","first-page":"e102","DOI":"10.1371\/journal.ppat.0030102","article-title":"Molecular basis of resistance to muramidase and cationic antimicrobial peptide activity of lysozyme in staphylococci.","volume":"3","author":"S Herbert","year":"2007","journal-title":"PLoS Pathog"},{"issue":"2","key":"ppat.1011536.ref073","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1128\/AAC.05054-11","article-title":"GraXSR proteins interact with the VraFG ABC transporter to form a five-component system required for cationic antimicrobial peptide sensing and resistance in Staphylococcus aureus","volume":"56","author":"M Falord","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"ppat.1011536.ref074","doi-asserted-by":"crossref","first-page":"e1009338","DOI":"10.1371\/journal.ppat.1009338","article-title":"The extracellular loop of the membrane permease VraG interacts with GraS to sense cationic antimicrobial peptides in Staphylococcus aureus","volume":"17","author":"J Cho","year":"2021","journal-title":"PLoS Pathog"},{"issue":"2","key":"ppat.1011536.ref075","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/mmi.12551","article-title":"Differential localization of LTA synthesis proteins and their interaction with the cell division machinery in Staphylococcus aureus","volume":"92","author":"NT Reichmann","year":"2014","journal-title":"Mol Microbiol"},{"issue":"16","key":"ppat.1011536.ref076","doi-asserted-by":"crossref","DOI":"10.1128\/JB.00149-20","article-title":"The length of lipoteichoic acid polymers controls Staphylococcus aureus cell size and envelope integrity","volume":"202","author":"AR Hesser","year":"2020","journal-title":"J Bacteriol"},{"issue":"46","key":"ppat.1011536.ref077","doi-asserted-by":"crossref","first-page":"18909","DOI":"10.1073\/pnas.1209126109","article-title":"Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids","volume":"109","author":"S Brown","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"ppat.1011536.ref078","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1074\/jbc.REV119.010155","article-title":"Uncovering the activities, biological roles, and regulation of bacterial cell wall hydrolases and tailoring enzymes","volume":"295","author":"T Do","year":"2020","journal-title":"J Biol Chem"},{"issue":"2","key":"ppat.1011536.ref079","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41564-019-0632-1","article-title":"Staphylococcus aureus cell growth and division are regulated by an amidase that trims peptides from uncrosslinked peptidoglycan","volume":"5","author":"T Do","year":"2020","journal-title":"Nat Microbiol"},{"issue":"1","key":"ppat.1011536.ref080","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1574-6968.2000.tb08877.x","article-title":"Triton X-100-induced lipoteichoic acid release is correlated with the methicillin resistance in Staphylococcus aureus","volume":"182","author":"K Ohta","year":"2000","journal-title":"FEMS Microbiol Lett"},{"issue":"1","key":"ppat.1011536.ref081","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02340-14","article-title":"The lipid-modifying multiple peptide resistance factor is an oligomer consisting of distinct interacting synthase and flippase subunits.","volume":"6","author":"CM Ernst","year":"2015","journal-title":"mBio"},{"key":"ppat.1011536.ref082","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.66376","article-title":"Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF.","volume":"11","author":"CJ Slavetinsky","year":"2022","journal-title":"Elife"},{"issue":"11","key":"ppat.1011536.ref083","doi-asserted-by":"crossref","first-page":"e1000660","DOI":"10.1371\/journal.ppat.1000660","article-title":"The bacterial defensin resistance protein MprF consists of separable domains for lipid lysinylation and antimicrobial peptide repulsion.","volume":"5","author":"CM Ernst","year":"2009","journal-title":"PLoS Pathog"},{"key":"ppat.1011536.ref084","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.3389\/fmicb.2018.01086","article-title":"Effect of a Point Mutation in mprF on Susceptibility to Daptomycin, Vancomycin, and Oxacillin in an MRSA Clinical Strain.","volume":"9","author":"FJ Chen","year":"2018","journal-title":"Front Microbiol."},{"issue":"14","key":"ppat.1011536.ref085","doi-asserted-by":"crossref","first-page":"e2123268119","DOI":"10.1073\/pnas.2123268119","article-title":"Conformational snapshots of the bacitracin sensing and resistance transporter BceAB","volume":"119","author":"NL George","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1011536.ref086","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/mmi.12637","article-title":"Accumulation of heptaprenyl diphosphate sensitizes Bacillus subtilis to bacitracin: implications for the mechanism of resistance mediated by the BceAB transporter","volume":"93","author":"AW Kingston","year":"2014","journal-title":"Mol Microbiol"},{"issue":"7","key":"ppat.1011536.ref087","doi-asserted-by":"crossref","first-page":"e21323","DOI":"10.1371\/journal.pone.0021323","article-title":"Investigation of the Staphylococcus aureus GraSR regulon reveals novel links to virulence, stress response and cell wall signal transduction pathways","volume":"6","author":"M Falord","year":"2011","journal-title":"PLoS One"},{"issue":"1","key":"ppat.1011536.ref088","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/0378-1119(91)90399-V","article-title":"Construction of single-copy integration vectors for Staphylococcus aureus","volume":"103","author":"CY Lee","year":"1991","journal-title":"Gene"},{"key":"ppat.1011536.ref089","first-page":"15","volume-title":"Approved standard, 12th ed. CLSI standard M02-A13","author":"CLSI","year":"2018"},{"key":"ppat.1011536.ref090","first-page":"27","volume-title":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 11th ed. CLSI standard M07-A11","author":"CLSI","year":"2018"},{"issue":"53","key":"ppat.1011536.ref091","doi-asserted-by":"crossref","first-page":"26970","DOI":"10.1074\/jbc.M116.747709","article-title":"New Insights into the Cyclic Di-adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic Dinucleotide for Acid Stress Resistance in Staphylococcus aureus.","volume":"291","author":"L Bowman","year":"2016","journal-title":"J Biol Chem"},{"key":"ppat.1011536.ref092","article-title":"Mutation of lipoprotein processing pathway gene lspA or inhibition of LspA activity by globomycin increases MRSA resistance to \u03b2-lactam antibiotics","volume":"2021","author":"C Fingleton","year":"2021","journal-title":"bioRxiv"},{"key":"ppat.1011536.ref093","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-1-4939-3676-2_2","article-title":"Ultra-Sensitive, High-Resolution Liquid Chromatography Methods for the High-Throughput Quantitative Analysis of Bacterial Cell Wall Chemistry and Structure.","volume":"1440","author":"L Alvarez","year":"2016","journal-title":"Methods Mol Biol"},{"issue":"1","key":"ppat.1011536.ref094","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/mmi.12266","article-title":"Peptidoglycan at its peaks: how chromatographic analyses can reveal bacterial cell wall structure and assembly","volume":"89","author":"SM Desmarais","year":"2013","journal-title":"Mol Microbiol"},{"issue":"1","key":"ppat.1011536.ref095","doi-asserted-by":"crossref","first-page":"e0355822","DOI":"10.1128\/mbio.03558-22","article-title":"Growth Arrest of Staphylococcus aureus Induces Daptomycin Tolerance via Cell Wall Remodelling.","volume":"14","author":"EVK Ledger","year":"2023","journal-title":"mBio"},{"issue":"1","key":"ppat.1011536.ref096","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1038\/s41467-022-29717-3","article-title":"Human serum triggers antibiotic tolerance in Staphylococcus aureus.","volume":"13","author":"EVK Ledger","year":"2022","journal-title":"Nat Commun"},{"issue":"4","key":"ppat.1011536.ref097","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/mmi.14433","article-title":"High-throughput transposon sequencing highlights the cell wall as an important barrier for osmotic stress in methicillin resistant Staphylococcus aureus and underlines a tailored response to different osmotic stressors","volume":"113","author":"CF Schuster","year":"2020","journal-title":"Mol Microbiol"},{"issue":"4","key":"ppat.1011536.ref098","doi-asserted-by":"crossref","first-page":"e10146","DOI":"10.1371\/journal.pone.0010146","article-title":"Identification of genes involved in polysaccharide-independent Staphylococcus aureus biofilm formation.","volume":"5","author":"BR Boles","year":"2010","journal-title":"PLoS One."},{"key":"ppat.1011536.ref099","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.carbpol.2016.09.075","article-title":"Development of in vitro resistance to chitosan is related to changes in cell envelope structure of Staphylococcus aureus","volume":"157","author":"D Raafat","year":"2017","journal-title":"Carbohydr Polym"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1011536","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T00:00:00Z","timestamp":1691020800000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011536","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T17:54:52Z","timestamp":1691085292000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011536"}},"subtitle":[],"editor":[{"given":"Gongyi","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,7,24]]},"references-count":99,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1011536","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.ppat.1011536","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,24]]}}}