title: Structure-guided design of cell wall biosynthesis inhibitors that overcome β-lactam resistance in Staphylococcus aureus (MRSA).
abstract: β-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis. Many pathogens express drug-insensitive PBPs rendering β-lactams ineffective, revealing a need for new types of PBP inhibitors active against resistant strains. We have identified alkyl boronic acids that are active against pathogens including methicillin-resistant S. aureus (MRSA). The crystal structures of PBP1b complexed to 11 different alkyl boronates demonstrate that in vivo efficacy correlates with the mode of inhibitor side chain binding. Staphylococcal membrane analyses reveal that the most potent alkyl boronate targets PBP1, an autolysis system regulator, and PBP2a, a low β-lactam affinity enzyme. This work demonstrates the potential of boronate-based PBP inhibitors for circumventing β-lactam resistance and opens avenues for the development of novel antibiotics that target Gram-positive pathogens.
authors: Bacterial Pathogenesis Group, Institut de Biologie Structurale, Université Grenoble I, France.
authors: Carlos
authors: C
authors: Contreras-Martel
authors: Ana
authors: A
authors: Amoroso
authors: Esther C Y
authors: EC
authors: Woon
authors: Astrid
authors: A
authors: Zervosen
authors: Steven
authors: S
authors: Inglis
authors: Alexandre
authors: A
authors: Martins
authors: Olivier
authors: O
authors: Verlaine
authors: Anna M
authors: AM
authors: Rydzik
authors: Viviana
authors: V
authors: Job
authors: André
authors: A
authors: Luxen
authors: Bernard
authors: B
authors: Joris
authors: Christopher J
authors: CJ
authors: Schofield
authors: Andréa
authors: A
authors: Dessen
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001897:Boronic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018440:beta-Lactam Resistance / Q000187:drug effects*; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001897:Boronic Acids; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams