Bimodal antibiotic susceptibilities in C. crescentus

SUMMARY

Cytoplasmic pentapeptide repeat proteins (PRPs) protect bacterial DNA gyrase from quinolone antibiotics. While some secreted PRPs are essential upon quinolone exposure, their role in the regulation of antibiotic resistance remains to be fully characterised. The authors show that a YjbI-type secreted PRP regulates antibiotic sensitivity, bimodally for small or large molecules, via modulation of 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 outer membrane via the previously uncharacterized TBDR BugA and its orthologs. Zinc stress triggers rapid proteolytic removal of Yjbl, activates expression of TBDRs, including BugA, and ultimately leads to replenishment of 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 β-helix. Taken together, these findings identify a role of YjbI as a cell surface-regulator of outer membrane composition and antibiotic sensitivity in a Gram-negative bacterium.

Full article: https://doi.org/10.1038/s44318-025-00668-x

WHY IS THIS IMPORTANT?

Antibiotic resistance in Gram-negative bacteria is partly due to their outer membrane, an asymmetric layer that acts as a permeability barrier. This study shows that a conserved surface protein called YjbI helps bacteria sense envelope stress and adjust that barrier. When YjbI is lost, bacteria become surprisingly sensitive to two opposite types of antibiotics: small drugs that stimulate drug-efflux pumps, and large antibiotics that normally cannot traverse the outer membrane. The researchers discovered that YjbI controls which nutrient transport proteins are present, including BugA, a newly identified gateway that allows large antibiotics like vancomycin to enter. Zinc stress temporarily removes YjbI, triggering adaptive changes to counter-balance the damage. Understanding how bacteria switch between resistance and sensitivity helps identify new ways to make antibiotics more effective and may guide strategies to overcome drug resistance in harmful bacteria, for example, via stress-activated nutrient-transporters.

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