Secreted ß-helix protein YjbI controls bimodal antibiotic susceptibilities from an asymmetric surface disposition
While cytoplasmic pentapeptide repeat proteins (PRPs) protect DNA gyrase from cytotoxic quinolones, the function of secreted (s)PRPs remains unknown. We show that a YjbI-type sPRP regulates antibiotic sensitivity, bimodally for small or large molecules, from the Caulobacter crescentus outer membrane (OM). YjbI silences two converging envelope stress pathways that globally reprogram the OM proteome via TonB-dependent receptors (TBDRs), periplasmic proteases and AcrAB-NodT, a multidrug efflux pump whose induction by small molecules and antibiotics is lethal to yjbI mutant cells. Loss of YjbI also confers sensitivity to vancomycin and bacitracin, two large peptidoglycan-targeting and zinc-binding antibiotics that permeate the OM via the uncharacterized TBDR BugA and orthologs. Zinc stress triggers YjbI's rapid proteolytic removal and transcriptionally activates BugA, other TBDRs, and (ultimately replenishes) YjbI. Molecular dynamics simulations and reactive thiol-probing imply an asymmetric surface disposition of YjbI, explaining the differential accessibility of its conserved cysteine pairs that flank the quadrilateral ß-helix. Overall design: Examination of HA-ChvI and HA-UzcR whole genome binding/occupancy (ChIP-Seq) in Caulobacter crescentus NA1000 (WT and yjbI::Tn mutant)