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Title | Adaptive β-lactam resistance from an inducible efflux pump that is post-translationally regulated by the DjlA co-chaperone. |
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Journal, issue, pages | PLoS Biol, Vol. 21, Issue 12, Page e3002040, Year 2023 |
Publish date | Dec 5, 2023 |
Authors | Jordan Costafrolaz / Gaël Panis / Bastien Casu / Silvia Ardissone / Laurence Degeorges / Martin Pilhofer / Patrick H Viollier / |
PubMed 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 ...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. |
External links | PLoS Biol / PubMed:38051727 / PubMed Central |
Methods | EM (tomography) |
Structure data | EMDB-18004: Cryo electron tomogram of Caulobacter crescentus - Delta-bla EMDB-18005: Cryo electron tomogram of Caulobacter crescentus - Delta-bla;tipT::Tn EMDB-18006: Cryo electron tomogram of Caulobacter crescentus - Delta-bla;pSRKacrAB::nodT EMDB-18007: Cryo electron tomogram of Caulobacter crescentus - Delta-bla;pSRKacrAB::nodT example 2 EMDB-18008: Cryo electron tomogram of Caulobacter crescentus - Delta-bla;tipR::Tn |
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