Abstract
We previously found that inhibition of the TCA cycle, either through mutations or chemical inhibition, increased toxT transcription in Vibrio cholerae. In this study, we found that the addition of malonate, an inhibitor of succinate dehydrogenase (SDH), decreased toxT transcription in V. cholerae, an observation inconsistent with the previous pattern observed. Unlike another SDH inhibitor, 2-thenoyltrifluoroacetone (TTFA), which increased toxT transcription and slightly inhibited V. cholerae growth, malonate inhibited toxT transcription in both the wild-type strain and TCA cycle mutants, suggesting malonate-mediated inhibition of virulence gene expression is independent to TCA cycle activity. Addition of malonate also inhibited ctxB and tcpA expressions but did not affect aphA, aphB, tcpP and toxR expressions. Malonate inhibited cholera toxin (CT) production in both V. cholerae classical biotype strains O395N1 and CA401, and El Tor biotype strain, N16961. Consistent with previous reports, we confirmed that these strains of V. cholerae did not utilize malonate as a primary carbon source. However, we found that the addition of malonate to the growth medium stimulated V. cholerae growth. All together, these results suggest that metabolizing malonate as a nutrient source negatively affects virulence gene expression in V. cholerae.
Highlights
Vibrio cholerae is the causative agent of cholera, a severe waterborne diarrheal disease
In V. cholerae, it has been shown that ToxT indirectly inhibits central metabolism pathways, including the TCA cycle and glycolysis [27]
We had previously found that the inhibition of the central metabolic pathway, the TCA cycle and the primary respiration-linked sodium pump, NADH:ubiquinone oxidoreductase (NQR), increased toxT transcription in V. cholerae [11,12]
Summary
Vibrio cholerae is the causative agent of cholera, a severe waterborne diarrheal disease. Toxin-coregulated pilus (TCP) and cholera toxin (CT) are essential for its virulence. TCP is a type IV pilus [1] that is required for colonization in the small intestine [2,3], whereas CT is a potent enterotoxin responsible for inducing cholera symptoms [4]. The expression of TCP and CT are positively regulated by an AraC-type transcriptional factor, ToxT [5,6]. Transcription of toxT is positively regulated by the membrane proteins ToxRS [5] and TcpPH [7]. The expression of tcpPH is positively regulated by the AphA [8] and AphB [9] transcriptional regulators
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