title: Resistance to antibiotics targeted to the bacterial cell wall.
abstract: Peptidoglycan is the main component of the bacterial cell wall. It is a complex, three-dimensional mesh that surrounds the entire cell and is composed of strands of alternating glycan units crosslinked by short peptides. Its biosynthetic machinery has been, for the past five decades, a preferred target for the discovery of antibacterials. Synthesis of the peptidoglycan occurs sequentially within three cellular compartments (cytoplasm, membrane, and periplasm), and inhibitors of proteins that catalyze each stage have been identified, although not all are applicable for clinical use. A number of these antimicrobials, however, have been rendered inactive by resistance mechanisms. The employment of structural biology techniques has been instrumental in the understanding of such processes, as well as the development of strategies to overcome them. This review provides an overview of resistance mechanisms developed toward antibiotics that target bacterial cell wall precursors and its biosynthetic machinery. Strategies toward the development of novel inhibitors that could overcome resistance are also discussed.
authors.affiliation: Institut de Biologie Structurale (IBS), Université Grenoble Alpes, 6 rue Jules Horowitz, 38027, Grenoble, France; Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Grenoble, France; Centre National de la Recherche Scientifique (CNRS), UMR 5075, Grenoble, France; Bijvoet Center for Biomolecular Research, Department of Biochemistry of Membranes, Utrecht University, Utrecht, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Nikolaidis
authors.forename: S
authors.initials: S
authors.lastname: Favini-Stabile
authors.forename: A
authors.initials: A
authors.lastname: Dessen
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002473:Cell Wall / Q000737:chemistry / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D010457:Peptidoglycan / Q000096:biosynthesis; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010457:Peptidoglycan; D065093:beta-Lactamase Inhibitors
keywords: Penicillin-Binding Proteins; antibiotic resistance; bacterial cell wall; cycloserine; fosfomycin; lipid II; β-lactamases