Abstract
It has long been recognized that the modification of penicillin-binding proteins (PBPs) to reduce their affinity for β-lactams is an important mechanism (target modification) by which Gram-positive cocci acquire antibiotic resistance. Among Gram-negative rods (GNR), however, this mechanism has been considered unusual, and restricted to clinically irrelevant laboratory mutants for most species. Using as a model Pseudomonas aeruginosa, high up on the list of pathogens causing life-threatening infections in hospitalized patients worldwide, we show that PBPs may also play a major role in β-lactam resistance in GNR, but through a totally distinct mechanism. Through a detailed genetic investigation, including whole-genome analysis approaches, we demonstrate that high-level (clinical) β-lactam resistance in vitro, in vivo, and in the clinical setting is driven by the inactivation of the dacB-encoded nonessential PBP4, which behaves as a trap target for β-lactams. The inactivation of this PBP is shown to determine a highly efficient and complex β-lactam resistance response, triggering overproduction of the chromosomal β-lactamase AmpC and the specific activation of the CreBC (BlrAB) two-component regulator, which in turn plays a major role in resistance. These findings are a major step forward in our understanding of β-lactam resistance biology, and, more importantly, they open up new perspectives on potential antibiotic targets for the treatment of infectious diseases.
Highlights
Decades after their discovery, b-lactams remain key components of our antimicrobial armamentarium for the treatment of infectious diseases
Using the pathogen Pseudomonas aeruginosa as a model microorganism, we show that high-level b-lactam resistance in vitro and in vivo frequently occurs through a previously unrecognized, totally distinct resistance pathway, driven by the mutational inactivation of a nonessential penicillin-binding proteins (PBPs) (PBP4) that behaves as a trap target for b-lactams
Concluding remarks Using P. aeruginosa as a model organism, we have shown that the most prevalent mutations causing immediate onset of high level blactam resistance are found in the dacB gene, encoding the nonessential PBP4
Summary
B-lactams remain key components of our antimicrobial armamentarium for the treatment of infectious diseases. Mutants showing constitutive high level AmpC production (AmpC derepressed mutants) are frequently selected during treatment with these b-lactams, leading to the failure of antimicrobial therapy [5,6]. In some natural strains of Enterobacteriaceae and P. aeruginosa [6,7,8,9], the inactivation of AmpD (cytosolic N-acetyl-anhydromuramyl-L-alanine amidase involved in peptidoglycan recycling [10,11,12]), and point mutations in AmpR (LysR-type transcriptional regulator required for ampC induction [13,14,15]) have been found to lead to AmpC overexpression, and to b-lactam resistance. Inactivation of the E. coli dacB ortholog, encoding the nonessential low molecular mass PBP4
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