title: Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
abstract: 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.
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, Instituto Universitario de Investigación en Ciencias de la Salud Palma de Mallorca, Spain.
authors.forename: Bartolomé
authors.initials: B
authors.lastname: Moya
authors.forename: Andreas
authors.initials: A
authors.lastname: Dötsch
authors.forename: Carlos
authors.initials: C
authors.lastname: Juan
authors.forename: Jesús
authors.initials: J
authors.lastname: Blázquez
authors.forename: Laura
authors.initials: L
authors.lastname: Zamorano
authors.forename: Susanne
authors.initials: S
authors.lastname: Haussler
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver