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

Published inPLoS biology, vol. 21, no. 12, e3002040
Publication date2023-12-05
First online date2023-12-05
Abstract

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. We 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, we 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. We 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.

Citation (ISO format)
COSTAFROLAZ, Jordan et al. Adaptive β-lactam resistance from an inducible efflux pump that is post-translationally regulated by the DjlA co-chaperone. In: PLoS biology, 2023, vol. 21, n° 12, p. e3002040. doi: 10.1371/journal.pbio.3002040
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ISSN of the journal1544-9173
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