{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T04:22:26Z","timestamp":1787458946572,"version":"build-2736575974"},"reference-count":123,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["#101072632"],"award-info":[{"award-number":["#101072632"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["#101072632"],"award-info":[{"award-number":["#101072632"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>The peptidoglycan (PG) sacculus of Gram-negative bacteria is continuously reorganized by a diverse enzymatic repertoire, including lytic transglycosylases, endopeptidases, carboxypeptidases, amidases and LD-transpeptidases, that operate alongside PG synthases to maintain envelope integrity throughout the cell cycle. This remodeling machinery has been extensively characterized in the context of growth and division and it is now emerging also as a key determinant of bacterial survival under non-growing and stress conditions. This review summarizes current knowledge on PG remodeling in Gram-negative bacteria, with emphasis on its regulation during stationary phase, environmental stress, and outer membrane perturbation. How these remodeling pathways, characterized by increased 3\u20133 cross-linking and enhanced PG\u2013outer membrane coupling, contribute to survival under \u03b2-lactam exposure and how related enzymatic configurations can give rise to antibiotic tolerance and resistance is also discussed. Finally, recent progress in targeting PG remodeling enzymes, particularly lytic transglycosylases and peptidases, as adjuvant strategies to potentiate existing antibiotics are reviewed. In summary, PG remodeling represents a mechanistically validated but still underexploited target for addressing antibiotic tolerance and resistance in Gram-negative pathogens.<\/jats:p>","DOI":"10.3390\/antibiotics15080815","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:31:59Z","timestamp":1787304719000},"page":"815","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peptidoglycan Remodeling in Gram-Negative Bacteria: From Stress Adaptation to Antibiotic Tolerance and Therapeutic Targeting"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8846-9805","authenticated-orcid":false,"given":"Theresa","family":"Strohhammer","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences \u201cRodolfo Paoletti\u201d, University of Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3996-4141","authenticated-orcid":false,"given":"Alessandra M.","family":"Martorana","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences \u201cRodolfo Paoletti\u201d, University of Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0903-8024","authenticated-orcid":false,"given":"Alessandra","family":"Polissi","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences \u201cRodolfo Paoletti\u201d, University of Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Westblade, L.F., Errington, J., and D\u00f6rr, T. (2020). Antibiotic Tolerance. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008892"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1042\/BST20230027","article-title":"Mechanisms Conferring Bacterial Cell Wall Variability and Adaptivity","volume":"52","author":"Torrens","year":"2024","journal-title":"Biochem. Soc. Trans."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/s41579-020-0366-3","article-title":"Regulation of Peptidoglycan Synthesis and Remodelling","volume":"18","author":"Egan","year":"2020","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1128\/MMBR.62.4.1435-1491.1998","article-title":"Protein Phylogenies and Signature Sequences: A Reappraisal of Evolutionary Relationships among Archaebacteria, Eubacteria, and Eukaryotes","volume":"62","author":"Gupta","year":"1998","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1128\/br.36.4.407-477.1972","article-title":"Peptidoglycan Types of Bacterial Cell Walls and Their Taxonomic Implications","volume":"36","author":"Schleifer","year":"1972","journal-title":"Bacteriol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1574-6976.2007.00088.x","article-title":"Structural Variation in the Glycan Strands of Bacterial Peptidoglycan","volume":"32","author":"Vollmer","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1128\/MMBR.62.1.181-203.1998","article-title":"Growth of the Stress-Bearing and Shape-Maintaining Murein Sacculus of Escherichia coli","volume":"62","year":"1998","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.1574-6976.2007.00094.x","article-title":"Peptidoglycan Structure and Architecture","volume":"32","author":"Vollmer","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4718","DOI":"10.1111\/febs.16066","article-title":"LD-transpeptidases: The Great Unknown among the Peptidoglycan Cross-linkers","volume":"289","author":"Aliashkevich","year":"2022","journal-title":"FEBS J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"fny199","DOI":"10.1093\/femsle\/fny199","article-title":"Lpp, the Braun Lipoprotein, Turns 50\u2014Major Achievements and Remaining Issues","volume":"365","author":"Asmar","year":"2018","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1432-1033.1970.tb00301.x","article-title":"The Murein-Lipoprotein Linkage in the Cell Wall of Escherichia coli","volume":"14","author":"Braun","year":"1970","journal-title":"Eur. J. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2416426121","DOI":"10.1073\/pnas.2416426121","article-title":"OmpA Controls Order in the Outer Membrane and Shares the Mechanical Load","volume":"121","author":"Benn","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/s41467-020-15083-5","article-title":"The Lipoprotein Pal Stabilises the Bacterial Outer Membrane during Constriction by a Mobilisation-and-Capture Mechanism","volume":"11","author":"Szczepaniak","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/j.1574-6976.2008.00104.x","article-title":"Cytoplasmic Steps of Peptidoglycan Biosynthesis","volume":"32","author":"Barreteau","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1111\/j.1574-6976.2007.00089.x","article-title":"The Biosynthesis of Peptidoglycan Lipid-Linked Intermediates","volume":"32","author":"Bouhss","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1038\/emboj.2011.61","article-title":"Identification of FtsW as a Transporter of Lipid-Linked Cell Wall Precursors across the Membrane","volume":"30","author":"Mohammadi","year":"2011","journal-title":"EMBO J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1128\/MMBR.62.4.1079-1093.1998","article-title":"Multimodular Penicillin-Binding Proteins: An Enigmatic Family of Orthologs and Paralogs","volume":"62","author":"Goffin","year":"1998","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/nature19331","article-title":"SEDS Proteins Are a Widespread Family of Bacterial Cell Wall Polymerases","volume":"537","author":"Meeske","year":"2016","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4782","DOI":"10.1128\/JB.00025-08","article-title":"Identification of the l,d -Transpeptidases for Peptidoglycan Cross-Linking in Escherichia coli","volume":"190","author":"Magnet","year":"2008","journal-title":"J. Bacteriol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Walenkiewicz, B., Alvarez, L., and Cava, F. (2026). LD-Transpeptidation in Bacterial Cell Walls: Biochemical Principles and Functional Diversity. Microbiol. Mol. Biol. Rev., e00090-24.","DOI":"10.1128\/mmbr.00090-24"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.1128\/JB.00084-07","article-title":"Identification of the L,D-Transpeptidases Responsible for Attachment of the Braun Lipoprotein to Escherichia coli Peptidoglycan","volume":"189","author":"Magnet","year":"2007","journal-title":"J. Bacteriol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e00836-21","DOI":"10.1128\/mBio.00836-21","article-title":"DpaA Detaches Braun\u2019s Lipoprotein from Peptidoglycan","volume":"12","author":"Winkle","year":"2021","journal-title":"mBio"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/emboj.2010.9","article-title":"Bacterial Actin MreB Assembles in Complex with Cell Shape Protein RodZ","volume":"29","author":"Johnson","year":"2010","journal-title":"EMBO J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.mib.2016.08.008","article-title":"Redefining the Roles of the FtsZ-Ring in Bacterial Cytokinesis","volume":"34","author":"Xiao","year":"2016","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.mib.2017.01.006","article-title":"Robust Peptidoglycan Growth by Dynamic and Variable Multi-Protein Complexes","volume":"36","author":"Pazos","year":"2017","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Vermassen, A., Leroy, S., Talon, R., Provot, C., Popowska, M., and Desvaux, M. (2019). Cell Wall Hydrolases in Bacteria: Insight on the Diversity of Cell Wall Amidases, Glycosidases and Peptidases Toward Peptidoglycan. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.00331"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nrmicro2677","article-title":"From the Regulation of Peptidoglycan Synthesis to Bacterial Growth and Morphology","volume":"10","author":"Typas","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1016\/j.bbamem.2007.06.007","article-title":"Murein (Peptidoglycan) Structure, Architecture and Biosynthesis in Escherichia coli","volume":"1778","author":"Vollmer","year":"2008","journal-title":"Biochim. Biophys. Acta (BBA) Biomembr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00428-22","DOI":"10.1128\/jb.00428-22","article-title":"Masters of Misdirection: Peptidoglycan Glycosidases in Bacterial Growth","volume":"205","author":"Weaver","year":"2023","journal-title":"J. Bacteriol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8326","DOI":"10.1128\/JB.186.24.8326-8336.2004","article-title":"Endopeptidase Penicillin-Binding Proteins 4 and 7 Play Auxiliary Roles in Determining Uniform Morphology of Escherichia coli","volume":"186","author":"Meberg","year":"2004","journal-title":"J. Bacteriol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s00726-020-02830-7","article-title":"Involvement of Penicillin-Binding Proteins in the Metabolism of a Bacterial Peptidoglycan Containing a Non-Canonical d-Amino Acid","volume":"52","author":"Miyamoto","year":"2020","journal-title":"Amino Acids"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1111\/mmi.12058","article-title":"Three Redundant Murein Endopeptidases Catalyse an Essential Cleavage Step in Peptidoglycan Synthesis of Escherichia coli K 12","volume":"86","author":"Singh","year":"2012","journal-title":"Mol. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.1128\/JB.183.10.3055-3064.2001","article-title":"Contributions of PBP 5 and DD-Carboxypeptidase Penicillin Binding Proteins to Maintenance of Cell Shape in Escherichia coli","volume":"183","author":"Nelson","year":"2001","journal-title":"J. Bacteriol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Obando, M.A., and D\u00f6rr, T. (2023). Novel Role for Peptidoglycan Carboxypeptidases in Maintaining the Balance between Bacterial Cell Wall Synthesis and Degradation. bioRxiv, bioRxiv:2023.07.12.548665.","DOI":"10.1101\/2023.07.12.548665"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e00819-16","DOI":"10.1128\/mBio.00819-16","article-title":"The Redundancy of Peptidoglycan Carboxypeptidases Ensures Robust Cell Shape Maintenance in Escherichia coli","volume":"7","author":"Peters","year":"2016","journal-title":"mBio"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5634","DOI":"10.1128\/JB.00446-07","article-title":"An Anhydro-N-Acetylmuramyl-L-Alanine Amidase with Broad Specificity Tethered to the Outer Membrane of Escherichia coli","volume":"189","author":"Uehara","year":"2007","journal-title":"J. Bacteriol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5094","DOI":"10.1128\/JB.00505-09","article-title":"LytM-Domain Factors Are Required for Daughter Cell Separation and Rapid Ampicillin-Induced Lysis in Escherichia coli","volume":"191","author":"Uehara","year":"2009","journal-title":"J. Bacteriol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11347","DOI":"10.1073\/pnas.1508536112","article-title":"Bacterial SPOR Domains Are Recruited to Septal Peptidoglycan by Binding to Glycan Strands That Lack Stem Peptides","volume":"112","author":"Yahashiri","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/j.1365-2958.2012.08103.x","article-title":"Cooperativity of Peptidoglycan Synthases Active in Bacterial Cell Elongation","volume":"85","author":"Banzhaf","year":"2012","journal-title":"Mol. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4799","DOI":"10.1128\/jb.173.15.4799-4813.1991","article-title":"Cloning, Mapping, and Characterization of the Escherichia coli Prc Gene, Which Is Involved in C-Terminal Processing of Penicillin-Binding Protein 3","volume":"173","author":"Hara","year":"1991","journal-title":"J. Bacteriol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Jeon, W.-J., and Cho, H. (2022). A Cell Wall Hydrolase MepH Is Negatively Regulated by Proteolysis Involving Prc and NlpI in Escherichia coli. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.878049"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10956","DOI":"10.1073\/pnas.1507760112","article-title":"Regulated Proteolysis of a Cross-Link\u2013Specific Peptidoglycan Hydrolase Contributes to Bacterial Morphogenesis","volume":"112","author":"Singh","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s42003-022-03355-3","article-title":"Structure-Based Inhibitor Design for Reshaping Bacterial Morphology","volume":"5","author":"Choi","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Sycuro, L.K., Wyckoff, T.J., Biboy, J., Born, P., Pincus, Z., Vollmer, W., and Salama, N.R. (2012). Multiple Peptidoglycan Modification Networks Modulate Helicobacter Pylori\u2019s Cell Shape, Motility, and Colonization Potential. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002603"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11685","DOI":"10.1074\/jbc.REV119.005593","article-title":"Trouble Is Coming: Signaling Pathways That Regulate General Stress Responses in Bacteria","volume":"294","author":"Gottesman","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Handler, S., and Kirkpatrick, C.L. (2024). New Layers of Regulation of the General Stress Response Sigma Factor RpoS. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1363955"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/1758-2229.12112","article-title":"sigmaS, a Major Player in the Response to Environmental Stresses in Escherichia coli: Role, Regulation and Mechanisms of Promoter Recognition","volume":"6","author":"Landini","year":"2014","journal-title":"Environ. Microbiol. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1128\/JB.187.5.1591-1603.2005","article-title":"Genome-Wide Analysis of the General Stress Response Network in Escherichia coli: SigmaS-Dependent Genes, Promoters, and Sigma Factor Selectivity","volume":"187","author":"Weber","year":"2005","journal-title":"J. Bacteriol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e00151-22","DOI":"10.1128\/mmbr.00151-22","article-title":"RpoS and the Bacterial General Stress Response","volume":"88","author":"Bouillet","year":"2024","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Mitchell, A.M., Wang, W., and Silhavy, T.J. (2017). Novel RpoS-Dependent Mechanisms Strengthen the Envelope Permeability Barrier during Stationary Phase. J. Bacteriol., 199.","DOI":"10.1128\/JB.00708-16"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1046\/j.1365-2958.1998.01077.x","article-title":"The ftsQ1p Gearbox Promoter of Escherichia coli Is a Major sigma S-dependent Promoter in the ddlB\u2014ftsA Region","volume":"30","author":"Ballesteros","year":"1998","journal-title":"Mol. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1128\/AAC.38.2.205","article-title":"Penicillin-Binding Proteins Are Regulated by rpoS during Transitions in Growth States of Escherichia coli","volume":"38","author":"Dougherty","year":"1994","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e02729-18","DOI":"10.1128\/mBio.02729-18","article-title":"Peptidoglycan Remodeling Enables Escherichia coli To Survive Severe Outer Membrane Assembly Defect","volume":"10","author":"Martorana","year":"2019","journal-title":"mBio"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"10088","DOI":"10.1016\/S0021-9258(19)81481-3","article-title":"The Composition of the Murein of Escherichia coli","volume":"263","author":"Glauner","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e19469","DOI":"10.7554\/eLife.19469","article-title":"Factors Essential for L,D-Transpeptidase-Mediated Peptidoglycan Cross-Linking and \u03b2-Lactam Resistance in Escherichia coli","volume":"5","author":"Hugonnet","year":"2016","journal-title":"eLife"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Mont\u00f3n Silva, A., Otten, C., Biboy, J., Breukink, E., VanNieuwenhze, M., Vollmer, W., and Den Blaauwen, T. (2018). The Fluorescent D-Amino Acid NADA as a Tool to Study the Conditional Activity of Transpeptidases in Escherichia coli. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.02101"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e05217-22","DOI":"10.1128\/spectrum.05217-22","article-title":"Characterization of Pseudomonas Aeruginosa L,D-Transpeptidases and Evaluation of Their Role in Peptidoglycan Adaptation to Biofilm Growth","volume":"11","author":"Barnier","year":"2023","journal-title":"Microbiol. Spectr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3442","DOI":"10.1038\/emboj.2011.246","article-title":"Distinct Pathways for Modification of the Bacterial Cell Wall by Non-canonical D-amino Acids","volume":"30","author":"Cava","year":"2011","journal-title":"EMBO J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1126\/science.1178123","article-title":"D-Amino Acids Govern Stationary Phase Cell Wall Remodeling in Bacteria","volume":"325","author":"Lam","year":"2009","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"107578","DOI":"10.1016\/j.celrep.2020.107578","article-title":"Modulation of Peptidoglycan Synthesis by Recycled Cell Wall Tetrapeptides","volume":"31","author":"Waldor","year":"2020","journal-title":"Cell Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/BF00383013","article-title":"Identification of the dadX Gene Coding for the Predominant Isozyme of Alanine Racemase in Escherichia coli K12","volume":"198","author":"Wild","year":"1985","journal-title":"Mol. Gen. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez, S.B., Castanheira, S., Pucciarelli, M.G., Cestero, J.J., Rico-P\u00e9rez, G., Paradela, A., Ayala, J.A., Vel\u00e1zquez, S., San-F\u00e9lix, A., and Cava, F. (2022). Peptidoglycan Editing in Non-Proliferating Intracellular Salmonella as Source of Interference with Immune Signaling. PLoS Pathog., 18.","DOI":"10.1371\/journal.ppat.1010241"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s00284-001-0062-0","article-title":"Modification of the Peptidoglycan of Escherichia coli in the Viable But Nonculturable State","volume":"44","author":"Signoretto","year":"2002","journal-title":"Curr. Microbiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.cell.2010.11.037","article-title":"Lipoprotein Cofactors Located in the Outer Membrane Activate Bacterial Cell Wall Polymerases","volume":"143","author":"Markovski","year":"2010","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e2108894118","DOI":"10.1073\/pnas.2108894118","article-title":"The LpoA Activator Is Required to Stimulate the Peptidoglycan Polymerase Activity of Its Cognate Cell Wall Synthase PBP1a","volume":"118","author":"Sardis","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/j.cell.2010.11.038","article-title":"Regulation of Peptidoglycan Synthesis by Outer-Membrane Proteins","volume":"143","author":"Typas","year":"2010","journal-title":"Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"100086","DOI":"10.1016\/j.tcsw.2022.100086","article-title":"Outer Membrane-Anchoring Enables LpoB to Regulate Peptidoglycan Synthesis Rate","volume":"8","author":"Kermani","year":"2022","journal-title":"Cell Surf."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6944","DOI":"10.1038\/s41467-025-62051-y","article-title":"The Hit-and-Run of Cell Wall Synthesis: LpoB Transiently Binds and Activates PBP1b through a Conserved Allosteric Switch","volume":"16","author":"Shlosman","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1038\/s41564-025-02058-9","article-title":"Peptidoglycan\u2013Outer Membrane Attachment Generates Periplasmic Pressure to Prevent Lysis in Gram-Negative Bacteria","volume":"10","author":"Deghelt","year":"2025","journal-title":"Nat. Microbiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/s41586-018-0344-3","article-title":"The Outer Membrane Is an Essential Load-Bearing Element in Gram-Negative Bacteria","volume":"559","author":"Rojas","year":"2018","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e00372-24","DOI":"10.1128\/aac.00372-24","article-title":"Lytic Transglycosylase Repertoire Diversity Enables Intrinsic Antibiotic Resistance and Daughter Cell Separation in Escherichia coli under Acidic Stress","volume":"68","author":"Son","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e00014-23","DOI":"10.1128\/spectrum.00014-23","article-title":"Coordinated and Distinct Roles of Peptidoglycan Carboxypeptidases DacC and DacA in Cell Growth and Shape Maintenance under Stress Conditions","volume":"11","author":"Choi","year":"2023","journal-title":"Microbiol. Spectr."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e00382-22","DOI":"10.1128\/jb.00382-22","article-title":"Peptidoglycan Remodeling by an L,D-Transpeptidase, LdtD during Cold Shock in Escherichia coli","volume":"205","author":"Nallamotu","year":"2023","journal-title":"J. Bacteriol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/s41579-020-00470-y","article-title":"The Stringent Response and Physiological Roles of (Pp)pGpp in Bacteria","volume":"19","author":"Irving","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1128\/jb.177.15.4224-4229.1995","article-title":"Direct Correlation between Overproduction of Guanosine 3\u2032,5\u2032-Bispyrophosphate (ppGpp) and Penicillin Tolerance in Escherichia coli","volume":"177","author":"Rodionov","year":"1995","journal-title":"J. Bacteriol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1139\/m80-253","article-title":"Inhibition of in Vitro Peptidoglycan Biosynthesis in Escherichia coli by Guanosine 5\u2032-Diphosphate 3\u2032-Diphosphate","volume":"26","author":"Ishiguro","year":"1980","journal-title":"Can. J. Microbiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2934","DOI":"10.1038\/s41598-019-39371-3","article-title":"(P)ppGpp-Mediated Stress Response Induced by Defects in Outer Membrane Biogenesis and ATP Production Promotes Survival in Escherichia coli","volume":"9","author":"Roghanian","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.cub.2021.12.033","article-title":"ppGpp Is a Bacterial Cell Size Regulator","volume":"32","author":"Grilli","year":"2022","journal-title":"Curr. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7937","DOI":"10.1038\/s41467-024-52325-2","article-title":"Control of Bacterial Cell Wall Autolysins by Peptidoglycan Crosslinking Mode","volume":"15","author":"Alvarez","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e01203-21","DOI":"10.1128\/spectrum.01203-21","article-title":"Hydroxyl Radical Overproduction in the Envelope: An Achilles\u2019 Heel in Peptidoglycan Synthesis","volume":"10","author":"Giacomucci","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"6790","DOI":"10.1074\/jbc.M808071200","article-title":"Oxidative Stress-Induced Peptidoglycan Deacetylase in Helicobacter Pylori","volume":"284","author":"Wang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"10786","DOI":"10.1073\/pnas.1809285115","article-title":"Copper Inhibits Peptidoglycan LD-Transpeptidases Suppressing \u03b2-Lactam Resistance Due to Bypass of Penicillin-Binding Proteins","volume":"115","author":"Peters","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1128\/JB.01037-10","article-title":"New Insights into the Lpt Machinery for Lipopolysaccharide Transport to the Cell Surface: LptA-LptC Interaction and LptA Stability as Sensors of a Properly Assembled Transenvelope Complex","volume":"193","author":"Sperandeo","year":"2011","journal-title":"J. Bacteriol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4460","DOI":"10.1128\/JB.00270-08","article-title":"Functional Analysis of the Protein Machinery Required for Transport of Lipopolysaccharide to the Outer Membrane of Escherichia coli","volume":"190","author":"Sperandeo","year":"2008","journal-title":"J. Bacteriol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Martorana, A.M., Motta, S., Di Silvestre, D., Falchi, F., Deh\u00f2, G., Mauri, P., Sperandeo, P., and Polissi, A. (2014). Dissecting Escherichia coli Outer Membrane Biogenesis Using Differential Proteomics. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100941"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/mmi.14712","article-title":"ActS Activates Peptidoglycan Amidases during Outer Membrane Stress in Escherichia coli","volume":"116","author":"Winkle","year":"2021","journal-title":"Mol. Microbiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/mmi.14711","article-title":"The Active Repertoire of Escherichia coli Peptidoglycan Amidases Varies with Physiochemical Environment","volume":"116","author":"Mueller","year":"2021","journal-title":"Mol. Microbiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4971","DOI":"10.1128\/AAC.00834-10","article-title":"colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production","volume":"54","author":"Moffatt","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e03099-21","DOI":"10.1128\/mBio.03099-21","article-title":"Acinetobacter baumannii Can Survive with an Outer Membrane Lacking Lipooligosaccharide Due to Structural Support from Elongasome Peptidoglycan Synthesis","volume":"12","author":"Simpson","year":"2021","journal-title":"mBio"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e02185-20","DOI":"10.1128\/mBio.02185-20","article-title":"Septal Class A Penicillin-Binding Protein Activity and LD-Transpeptidases Mediate Selection of colistin-Resistant Lipooligosaccharide-Deficient Acinetobacter baumannii","volume":"12","author":"Kang","year":"2021","journal-title":"mBio"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e00331-25","DOI":"10.1128\/jb.00331-25","article-title":"Molecular Interplay between Peptidoglycan Integrity and Outer Membrane Asymmetry in Maintaining Cell Envelope Homeostasis","volume":"207","author":"Nandy","year":"2025","journal-title":"J. Bacteriol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"8009","DOI":"10.1073\/pnas.0903229106","article-title":"An ABC Transport System That Maintains Lipid Asymmetry in the Gram-Negative Outer Membrane","volume":"106","author":"Malinverni","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"117623","DOI":"10.1016\/j.celrep.2026.117623","article-title":"Outer Membrane Remodeling via Lipid-Peptidoglycan Crosstalk Enables Lipooligosaccharide-Deficient colistin Resistance","volume":"45","author":"Furlan","year":"2026","journal-title":"Cell Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1128\/jb.167.3.759-765.1986","article-title":"Transglycosylase and Endopeptidase Participate in the Degradation of Murein during Autolysis of Escherichia coli","volume":"167","author":"Kitano","year":"1986","journal-title":"J. Bacteriol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0163-7258(85)90062-2","article-title":"Mode of Action of \u03b2-Lactam Antibiotics","volume":"27","author":"Tipper","year":"1985","journal-title":"Pharmacol. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1146\/annurev.mi.38.100184.002011","article-title":"The Structure and Mode of Action of Glycopeptide Antibiotics of the Vancomycin Group","volume":"38","author":"Barna","year":"1984","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1128\/AAC.39.4.812","article-title":"Target for Bacteriostatic and Bactericidal Activities of Beta-Lactam Antibiotics against Escherichia coli Resides in Different Penicillin-Binding Proteins","volume":"39","author":"Satta","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1046\/j.1365-2958.2001.02499.x","article-title":"Involvement of N-acetylmuramyl-L-alanine Amidases in Cell Separation and Antibiotic-induced Autolysis of Escherichia coli","volume":"41","author":"Heidrich","year":"2001","journal-title":"Mol. Microbiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3425","DOI":"10.1128\/jb.173.11.3425-3431.1991","article-title":"Analysis of Murein and Murein Precursors during Antibiotic-Induced Lysis of Escherichia coli","volume":"173","author":"Kohlrausch","year":"1991","journal-title":"J. Bacteriol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1016\/j.cell.2014.11.017","article-title":"Beta-Lactam Antibiotics Induce a Lethal Malfunctioning of the Bacterial Cell Wall Synthesis Machinery","volume":"159","author":"Cho","year":"2014","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/nyas.14541","article-title":"Understanding Tolerance to Cell Wall\u2013Active Antibiotics","volume":"1496","year":"2021","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"D\u00f6rr, T., Davis, B.M., and Waldor, M.K. (2015). Endopeptidase-Mediated Beta Lactam Tolerance. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004850"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1073\/pnas.1520333113","article-title":"A Cell Wall Damage Response Mediated by a Sensor Kinase\/Response Regulator Pair Enables Beta-Lactam Tolerance","volume":"113","author":"Alvarez","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"EMBR202051790","DOI":"10.15252\/embr.202051790","article-title":"A Multifaceted Cellular Damage Repair and Prevention Pathway Promotes High-Level Tolerance to \u03b2-Lactam Antibiotics","volume":"22","author":"Shin","year":"2021","journal-title":"EMBO Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e00277-26","DOI":"10.1128\/spectrum.00277-26","article-title":"Tail-Specific Protease (Tsp)-Mediated Envelope Remodeling and Beta-Lactam Tolerance in Escherichia coli","volume":"14","author":"Narzary","year":"2026","journal-title":"Microbiol. Spectr."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e01326-18","DOI":"10.1128\/AAC.01326-18","article-title":"Genetic Determinants of Penicillin Tolerance in Vibrio Cholerae","volume":"62","author":"Weaver","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Thomson, N.M., Turner, A.K., Yasir, M., Bastkowski, S., Lott, M., Webber, M.A., and Charles, I.G. (2022). A Whole-Genome Assay Identifies Four Principal Gene Functions That Confer Tolerance of Meropenem Stress upon Escherichia coli. Front. Antibiot., 1.","DOI":"10.3389\/frabi.2022.957942"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e00068-18","DOI":"10.1128\/AAC.00068-18","article-title":"Determinants of Extreme \u03b2-Lactam Tolerance in the Burkholderia Pseudomallei Complex","volume":"62","author":"Held","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e01734-22","DOI":"10.1128\/spectrum.01734-22","article-title":"Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic \u03b2-Lactam and Vancomycin Resistance","volume":"10","author":"Park","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/1348-0421.13227","article-title":"Lytic Transglycosylase Deficiency Increases Susceptibility to \u03b2-lactam Antibiotics But Reduces Susceptibility to Vancomycin in Escherichia coli","volume":"69","author":"Kimura","year":"2025","journal-title":"Microbiol. Immunol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"102562","DOI":"10.1016\/j.cbpa.2024.102562","article-title":"Bacterial Peptidoglycan as a Living Polymer","volume":"84","author":"Fisher","year":"2025","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1080\/14728222.2025.2608020","article-title":"Understanding How Bacterial Cell Wall Peptidoglycan Metabolism Can Be Used to Develop Antimicrobial Strategies","volume":"29","author":"Melotti","year":"2025","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"102480","DOI":"10.1016\/j.sbi.2022.102480","article-title":"The Mechanistic Landscape of Lytic Transglycosylase as Targets for Antibacterial Therapy","volume":"77","author":"Soriano","year":"2022","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e73178","DOI":"10.7554\/eLife.73178","article-title":"Lytic Transglycosylases Mitigate Periplasmic Crowding by Degrading Soluble Cell Wall Turnover Products","volume":"11","author":"Weaver","year":"2022","journal-title":"eLife"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1089\/mdr.2011.0231","article-title":"The Effect of Bulgecin A on Peptidoglycan Metabolism and Physiology of Helicobacter pylori","volume":"18","author":"Bonis","year":"2012","journal-title":"Microb. Drug Resist."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Williams, A., Wheeler, R., Thiriau, C., Haouz, A., Taha, M., and Boneca, I. (2017). Bulgecin A: The Key to a Broad-Spectrum Inhibitor That Targets Lytic Transglycosylases. Antibiotics, 6.","DOI":"10.3390\/antibiotics6010008"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.2147\/DDDT.S110193","article-title":"Bulgecin A as a \u03b2-Lactam Enhancer for Carbapenem-Resistant Pseudomonas aeruginosa and Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates Containing Various Resistance Mechanisms","volume":"10","author":"Skalweit","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1021\/acsinfecdis.8b00105","article-title":"Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the \u03b2-Lactam Antibiotics","volume":"4","author":"Tomoshige","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Kim, C., Tomoshige, S., Lee, M., Zgurskaya, H.I., and Mobashery, S. (2023). Penetration through Outer Membrane and Efflux Potential in Pseudomonas Aeruginosa of Bulgecin A as an Adjuvant to \u03b2-Lactam Antibiotics. Antibiotics, 12.","DOI":"10.3390\/antibiotics12020358"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1021\/acschembio.5b01039","article-title":"A Bacterial Cell Shape-Determining Inhibitor","volume":"11","author":"Liu","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"100947","DOI":"10.1016\/j.lanmic.2024.07.010","article-title":"Antimicrobial Resistance: A Concise Update","volume":"6","author":"Ho","year":"2025","journal-title":"Lancet Microbe"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.chom.2026.06.007","article-title":"Mining the Code of Life for New Antibiotics","volume":"34","author":"Crysler","year":"2026","journal-title":"Cell Host Microbe"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/s41586-020-1990-9","article-title":"Evolution-Guided Discovery of Antibiotics That Inhibit Peptidoglycan Remodelling","volume":"578","author":"Culp","year":"2020","journal-title":"Nature"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/8\/815\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T04:16:56Z","timestamp":1787458616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/8\/815"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":123,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["antibiotics15080815"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics15080815","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]}}}