Adaptive β-lactam resistance from an inducible efflux pump that is post-translationally regulated by the DjlA co-chaperone

SUMMARY

The acquisition of multidrug resistance (MDR) determinants jeopardizes treatment of bacterial infections with antibiotics. The tripartite efflux pump AcrAB-NodT confers adaptive MDR in the polarized α-proteobacterium Caulobacter crescentus via transcriptional induction by first-generation quinolone antibiotics. The authors of this article, published in PLOSBiology and led by GCIR member Professor Patrick Viollier, discovered that overexpression of AcrAB-NodT by mutation or exogenous inducers confers resistance to cephalosporin and penicillin (β-lactam) antibiotics. Combining 2-step mutagenesis-sequencing (Mut-Seq) and cephalosporin-resistant point mutants, they dissected how TipR uses a common operator of the divergent tipR and acrAB-nodT promoter for adaptive and/or potentiated AcrAB-NodT-directed efflux. Chemical screening identified diverse compounds that interfere with DNA binding by TipR or induce its dependent proteolytic turnover. They found that long-term induction of AcrAB-NodT deforms the envelope and that homeostatic control by TipR includes co-induction of the DnaJ-like co-chaperone DjlA, boosting pump assembly and/or capacity in anticipation of envelope stress. Thus, the adaptive MDR regulatory circuitry reconciles drug efflux with co-chaperone function for trans-envelope assemblies and maintenance.

Why is this important?

Efflux pumps that expel antibiotics are major problematic determinants of multidrug-resistant bacteria isolated from hospitalized patients. Some antibiotics can augment the synthesis of efflux pumps, a phenomenon referred to as adaptive antibiotic resistance. Here, researchers from the Department of Microbiology and Molecular Medicine at the University of Geneva Faculty of Medicine discovered that induction of the tripartite AcrAB-NodT efflux pump found in Gram-negative bacteria is coordinated with synthesis of DjlA, an HSP70 co-chaperone that prevents aggregation of the co-expressed AcrAB-NodT components into unusable deposits. With the newly described role of DjlA in boosting AcrAB-NodT, small molecule inhibitors of DjlA could emerge as an effective strategy to curb adaptive multi-drug resistance of Gram-negative pathogens.

News