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MpeR regulation in Neisseria gonorrhoeae (F19) through an iron-responsive mechanism

ABSTRACT: Previous studies have shown that the MpeR transcriptional regulator produced by Neisseria gonorrhoeae represses expression of mtrF, which encodes a putative inner membrane protein that works with the MtrC-MtrD-MtrE efflux pump to allow gonococci to resist high levels of multiple hydrophobic antimicrobials. Regulation of mpeR has been reported to occur by an iron-dependent mechanism involving Fur (Ferric uptake regulator). Collectively, these observations suggest the presence of an interconnected regulatory system in gonococci that modulates expression of drug efflux pump protein-encoding genes in an iron-responsive manner. Herein, we describe this connection and report that levels of gonococcal resistance to a substrate of the mtrCDE-encoded efflux pump can be modulated by MpeR and the availability of free iron. Using microarray analysis, we found that the mtrR gene, which encodes the direct transcriptional repressor (MtrR) of mtrCDE, is an MpeR-repressed determinant in the late-logarithmic phase of growth when free iron levels would be reduced due to bacterial consumption. MpeR-mediated repression of mtrR appeared to be direct, as judged by DNA-binding analyses, and was enhanced by conditions of iron-limitation, which resulted in increased expression of the mtrCDE efflux pump operon. Taken together, our results indicate that both genetic and physiologic parameters can influence expression of the mtr efflux system and that these can modulate levels of gonococcal susceptibility to efflux pump substrates.

ORGANISM(S): Neisseria gonorrhoeae

PROVIDER: GSE32717 | GEO | 2012/04/04

SECONDARY ACCESSION(S): PRJNA146985

REPOSITORIES: GEO

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Project description:Carbon catabolite repression (CCR) is a gene regulation process that allows bacteria to use carbon-energy sources in a hierarchical manner. Thus, the presence of a preferred sugar, usually D-glucose, results in downregulation of genes participating in the transport and catabolic pathways of secondary carbon sources. Further, CCR controls the expression of global regulators that control expression of many genes involved in multiple aspects of bacterial physiology such as stress response proteins and virulence factors. The human-restricted pathogen Neisseria gonorrhoeae can rely upon a limited number of carbon-energy sources, including glucose and lactate and both are available within its infection niches. We recently reported that expression of the L-lactate permease-encoding gene lctP is subjected to glucose repression within physiological concentrations. However, the transducing mechanism or the gene that connect glucose with lctP promoter repression remained unknown. To address this issue, we performed an RNA-Seq analysis to determine the transcriptional landscape of gonococci due to changes in glucose or lactate concentrations in the growth media. Glucose was found to regulate 144 genes (5.5% of total genes in the genome) while lactate influenced the expression of 434 (16.5%) genes with an overlap of 97 genes between the two sugars. Both, glucose and lactate were found to upregulate genes involved in protein translation, a high energy consumption cellular function. Individually, glucose enhanced genes participating in glycolysis and repressed genes in the tricarboxylic acid (TCA) cycle, while lactate enhanced genes encoding respiratory enzymes and ATP synthase. Interestingly, lactate was found to repress expression of several genes encoding known gonococcal virulence factors such as tbpAB encoding the transferrin-binding proteins; the tonB and exbBD genes encoding the membrane energy transfer complex TonB-ExbB-ExbD required for many outer membrane transport systems; katA encoding an important H2O2-inducible catalase and to upregulate mtrR encoding the master repressor of the mtrCDE antimicrobial efflux pump genes. Moreover, glucose repressed mntC encoding a Zn/Mn ABC transporter and lctP, both required for resistance to killing by H2O2. These results set the framework to determine important gonococci virulent factor genes whose expression can be modulated by CCR as well as to discover the corresponding CCR regulators that control such genes.

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MpeR regulation in Neisseria gonorrhoeae (F19) through an iron-responsive mechanism

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