Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein

• Published in: PLoS pathogens 2009-03, Vol.5 (3), p.e1000353-e1000353
• Main Authors: Moya, Bartolomé, Dötsch, Andreas, Juan, Carlos, Blázquez, Jesús, Zamorano, Laura, Haussler, Susanne, Oliver, Antonio
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Proteins - genetics; Beta lactam antibiotics; beta-Lactam Resistance - genetics; beta-Lactamases - genetics; Binding proteins; Communicable diseases; Comparative Genomic Hybridization; Drug resistance in microorganisms; Drug therapy; Gene Expression; Gene Expression Regulation, Bacterial - genetics; Genetic aspects; Health aspects; Humans; Mice; Microbiology; Microbiology/Medical Microbiology; Microbiology/Microbial Evolution and Genomics; Microbiology/Microbial Physiology and Metabolism; Mutation; Oligonucleotide Array Sequence Analysis; Penicillin-Binding Proteins - genetics; Physiological aspects; Pseudomonas aeruginosa; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000353

It has long been recognized that the modification of penicillin-binding proteins (PBPs) to reduce their affinity for beta-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 beta-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) beta-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 beta-lactams. The inactivation of this PBP is shown to determine a highly efficient and complex beta-lactam resistance response, triggering overproduction of the chromosomal beta-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 beta-lactam resistance biology, and, more importantly, they open up new perspectives on potential antibiotic targets for the treatment of infectious diseases.