β-Lactam Resistance Response Triggered by Inactivation of a Nonessential Penicillin-Binding Protein

PLoS Pathogens

Jesús Blázquez¹  Andreas Dötsch²  Susanne Haussler²  Carlos Juan³  Laura Zamorano³  Antonio Oliver³  Bartolomé Moya³ 

[1] Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Campus UAM, Madrid, Spain;Helmholtz Centre for Infection Research, Braunschweig, Germany;Servicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS) Palma de Mallorca, Spain

关键词: Pseudomonas aeruginosa;    Antibiotics;    Antibiotic resistance;    Regulator genes;    Point mutation;    Gene expression;    Mutation detection;    Polymerase chain reaction;   

DOI  :  10.1371/journal.ppat.1000353

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY