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

Autor: Costafrolaz, Jordan, Panis, Gaël, Casu, Bastien, Ardissone, Silvia, Degeorges, Laurence, Pilhofer, Martin, Viollier, Patrick H.
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Zdroj: PLoS Biology; 12/5/2023, Vol. 21 Issue 12, p1-31, 31p
Abstrakt: 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. The efflux pump AcrAB-NodT confers adaptive multidrug resistance in the α-proteobacterium Caulobacter crescentus when the TipR repressor is antagonized by quinolone antibiotics; although long-term expression of AcrAB-NodT deforms the envelope, this study shows that homeostatic control by TipR includes co-induction of the co-chaperone DjlA, which boosts efflux pump assembly in anticipation of envelope stress. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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