Abstract
ABSTRACTResistance-nodulation-division (RND) superfamily efflux systems have been widely studied for their role in antibiotic resistance, but their native biological functions remain poorly understood. We previously showed that loss of RND-mediated efflux in Vibrio cholerae resulted in activation of the Cpx two-component regulatory system, which mediates adaptation to stress resulting from misfolded membrane proteins. Here, we investigated the mechanism linking RND-mediated efflux to the Cpx response. We performed transposon mutagenesis screening of RND-deficient V. cholerae to identify Cpx suppressors. Suppressor mutations mapped to genes involved in the biosynthesis of the catechol siderophore vibriobactin. We subsequently demonstrated that vibriobactin secretion is impaired in mutants lacking the VexGH RND efflux system and that impaired vibriobactin secretion is responsible for Cpx system activation, suggesting that VexGH secretes vibriobactin. This conclusion was bolstered by results showing that vexGH expression is induced by iron limitation and that vexH-deficient cells exhibit reduced fitness during growth under iron-limiting conditions. Our results support a model where VexGH contributes to cellular homeostasis by effluxing vibriobactin. In the absence of vexGH, retained vibriobactin appears to chelate iron from iron-rich components of the respiratory chain, with the deferrated proteins functioning to activate the Cpx response. Our collective results demonstrate that a native function of the V. cholerae VexGH RND efflux system is in vibriobactin secretion and that vibriobactin efflux is critical for maintenance of cellular homeostasis.
Highlights
Resistance-nodulation-division (RND) superfamily efflux systems have been widely studied for their role in antibiotic resistance, but their native biological functions remain poorly understood
Vibriobactin is a catechol siderophore utilized for iron acquisition and is the only known siderophore produced by V. cholerae [12]
All four of the suppressor genes are regulated in response to iron [15, 16], suggesting that RND efflux-dependent activation of the Cpx system might be linked to vibriobactin production and/or iron homeostasis
Summary
Resistance-nodulation-division (RND) superfamily efflux systems have been widely studied for their role in antibiotic resistance, but their native biological functions remain poorly understood. The ability of V. cholerae to colonize and replicate in the human gastrointestinal (GI) tract is dependent upon its ability to adapt to its environment This includes overcoming colonization barriers provided by the presence of toxic antimicrobial compounds such as bile salts, fatty acids, and products of the innate immune system. Many of these compounds serve as environmental cues that activate the expression of adaptive responses in V. cholerae that facilitate survival and replication in the GI tract. This is accomplished by a multifactorial response that includes the expression of active efflux systems, reduced outer membrane permeability, and the expression of stress response systems that mitigate cellular damage resulting from exposure to toxic molecules [3]
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