RavA-ViaA linksVibrio choleraeCpx- and Zra2- envelope stress to antibiotic response

Abstract

AbstractRavA-ViaA were reported to play a role in aminoglycoside sensitivity but the mechanisms remain elusive. Here, we performed competition and survival experiments to confirm that deletion ofravA-viaAincreases tolerance of the Gram-negative pathogenVibrio choleraeto low and high aminoglycoside concentrations, during aerobic growth. Using high throughput strategies in this species, we identify Cpx and Zra2 two-component systems as new partners of RavA-ViaA. We show that the aminoglycoside tolerance ofΔravviarequires the presence of these membrane stress sensing two-component systems. We propose that deletion of the RavA-ViaA function facilitates the response aminoglycosides because of a pre-activated state of Cpx and Zra2 membrane stress response systems. We also find an impact of these genes on polymyxin B sensitivity and vancomycin resistance, and we show that simultaneous inactivation ofravviafunction together with envelope stress response systems leads to outer membrane permeabilization. Vancomycin is mostly used for Gram-positive because of its low efficiency for crossing the Gram-negative outer membrane. Targeting of theravA-viaAoperon for inactivation could be a future strategy to allow uptake of vancomycin into multidrug resistant Gram-negative bacteria.