Structural, biochemical andin vivocharacterization of MtrR-mediated resistance to innate antimicrobials by the human pathogenNeisseria gonorrhoeae.
2019
Neisseria gonorrhoeaeresponds to host-derived antimicrobials by inducing the expression of the mtrCDE-encoded multidrug efflux pump, which expels
microbicidessuch as bile salts, fatty acids, and multiple extrinsically administered drugs from the cell. In the absence of these cytotoxins, the
TetR-family member,
MtrR, represses the mtrCDE genes. Although antimicrobial-dependent
derepressionof mtrCDE is clear, the physiological inducers of
MtrRare unknown. Here, we report the crystal structure of an induced form of
MtrR. In the binding pocket of
MtrR, we observe electron density that we hypothesize is cyclohexyl-
3-aminopropanesulfonic acid(CAPS), a component of the crystallization reagent. Using the
MtrR-CAPS structure as an inducer-bound template, we hypothesized that bile salts, which bear significant chemical resemblance to CAPS, are physiologically relevant inducers. Indeed, characterization of
MtrR-
chenodeoxycholateand
MtrR-taurodeoxycholate interaction, both in vitro and in vivo, revealed these bile salts, but not glyocholate or taurocholate, bind
MtrRtightly and can act as bona fide inducers. Furthermore, two residues, W136 and R176, were shown to be important in binding
chenodeoxycholate, but not taurodeoxycholate, suggesting different binding modes of these bile salts. These data provide insight into a crucial mechanism utilized by this pathogen to overcome innate human defences. IMPORTANCENeisseria gonorrhoeae causes significant disease burden worldwide and a meteoric rise in its multidrug resistance has reduced the efficacy of antibiotics previously or currently approved for therapy of gonorrheal infections. Multidrug efflux pump MtrCDE transports multiple drugs and host-derived antimicrobials from the bacterial cell and confers survival advantage to the pathogen within the host. Transcription of this pump is repressed by
MtrR, but relieved by the cytosolic influx of antimicrobials. Here, we describe the structure of induced
MtrRand use this structure to identify bile salts as physiological inducers of
MtrR. These findings provide a mechanistic basis for antimicrobial sensing and gonococcal protection by
MtrRthrough the
derepressionof mtrCDE expression after exposure to intrinsic and clinically applied antimicrobials.
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