6of0

Publication Abstract from PubMed

Neisseria gonorrhoeae responds to host-derived antimicrobials by inducing the expression of the mtrCDE-encoded multidrug efflux pump, which expels microbicides such 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 derepression of mtrCDE is clear, the physiological inducers of MtrR are 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-chenodeoxycholate and MtrR-taurodeoxycholate interaction, both in vitro and in vivo, revealed these bile salts, but not glyocholate or taurocholate, bind MtrR tightly 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.IMPORTANCE Neisseria 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 MtrR and 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 MtrR through the derepression of mtrCDE expression after exposure to intrinsic and clinically applied antimicrobials.

Structural, biochemical and in vivo characterization of MtrR-mediated resistance to innate antimicrobials by the human pathogen Neisseria gonorrhoeae.,Beggs GA, Zalucki YM, Brown NG, Rastegari S, Phillips RK, Palzkill T, Shafer W, Kumaraswami M, Brennan RG J Bacteriol. 2019 Jul 22. pii: JB.00401-19. doi: 10.1128/JB.00401-19. PMID:31331979^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.