title: Resistance to β-lactam antibiotics conferred by point mutations in penicillin-binding proteins PBP3, PBP4 and PBP6 in Salmonella enterica.
abstract: Penicillin-binding proteins (PBPs) are enzymes responsible for the polymerization of the glycan strand and the cross-linking between glycan chains as well as the target proteins for β-lactam antibiotics. Mutational alterations in PBPs can confer resistance either by reducing binding of the antibiotic to the active site or by evolving a β-lactamase activity that degrades the antibiotic. As no systematic studies have been performed to examine the potential of all PBPs present in one bacterial species to evolve increased resistance against β-lactam antibiotics, we explored the ability of fifteen different defined or putative PBPs in Salmonella enterica to acquire increased resistance against penicillin G. We could after mutagenesis and selection in presence of penicillin G isolate mutants with amino-acid substitutions in the PBPs, FtsI, DacB and DacC (corresponding to PBP3, PBP4 and PBP6) with increased resistance against β-lactam antibiotics. Our results suggest that: (i) most evolved PBPs became 'generalists" with increased resistance against several different classes of β-lactam antibiotics, (ii) synergistic interactions between mutations conferring antibiotic resistance are common and (iii) the mechanism of resistance of these mutants could be to make the active site more accessible for water allowing hydrolysis or less binding to β-lactam antibiotics.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Song
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Selmer
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Dan I
authors.initials: DI
authors.lastname: Andersson
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D010400:Penicillin G / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D019779:Salmonella enterica / Q000187:drug effects* / Q000235:genetics*; D018440:beta-Lactam Resistance / Q000235:genetics*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams; D010400:Penicillin G