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AcrAB multidrug efflux pump regulation in Salmonella enterica serovar Typhimurium by RamA in response to environmental signals.

Nikaido E, Yamaguchi A, Nishino K - J. Biol. Chem. (2008)

Bottom Line: Among these pumps, AcrAB is effective in generating drug resistance and has wide substrate specificity.Other regulators of acrAB such as MarA, SoxS, Rob, SdiA, and AcrR did not contribute to acrAB induction by indole in Salmonella.Our results suggest that RamA controls the Salmonella AcrAB-TolC multidrug efflux system through dual regulatory modes in response to environmental signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.

ABSTRACT
Salmonella enterica serovar Typhimurium has at least nine multidrug efflux pumps. Among these pumps, AcrAB is effective in generating drug resistance and has wide substrate specificity. Here we report that indole, bile, and an Escherichia coli conditioned medium induced the AcrAB pump in Salmonella through a specific regulator, RamA. The RamA-binding sites were located in the upstream regions of acrAB and tolC. RamA was required for indole induction of acrAB. Other regulators of acrAB such as MarA, SoxS, Rob, SdiA, and AcrR did not contribute to acrAB induction by indole in Salmonella. Indole activated ramA transcription, and overproduction of RamA caused increased acrAB expression. In contrast, induction of ramA was not required for induction of acrAB by bile. Cholic acid binds to RamA, and we suggest that bile acts by altering pre-existing RamA. This points to two different AcrAB regulatory modes through RamA. Our results suggest that RamA controls the Salmonella AcrAB-TolC multidrug efflux system through dual regulatory modes in response to environmental signals.

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Proposed model for the expression of acrA and acrB multidrug efflux genes by RamA. In one pathway, bile may bind to the RamA protein, which is then converted from a low to a high activity state. In the other path, indole may activate ramA transcription to directly induce acrA and acrB.
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fig11: Proposed model for the expression of acrA and acrB multidrug efflux genes by RamA. In one pathway, bile may bind to the RamA protein, which is then converted from a low to a high activity state. In the other path, indole may activate ramA transcription to directly induce acrA and acrB.

Mentions: We also suggest the existence of a different induction mechanism for acrAB via the RamA regulator (Fig. 11). Indole was shown to induce ramA expression (Fig. 9), and such an increased expression of ramA can induce acrAB (Fig. 6A). On the other hand, bile did not affect expression of ramA (Fig. 9), but it did bind to RamA (Fig. 11). This is reminiscent of the binding of bile to the Rob protein involved in regulation of acrAB in E. coli (31). We also suggest that the N-terminal domain of RamA may be required for binding of bile because cholic acid did not bind to the truncated RamA (Fig. 10). Our results suggest a mechanism in which RamA can change between an “activated state” and an “overexpressed state” in response to environmental signals, thereby inducing the AcrAB-TolC system (Fig. 11). Thus, RamA can be converted from a low activity state to a high activity state in response to bile. We also suggest that Salmonella may have an additional sensor for indole that controls ramA expression (Fig. 11).


AcrAB multidrug efflux pump regulation in Salmonella enterica serovar Typhimurium by RamA in response to environmental signals.

Nikaido E, Yamaguchi A, Nishino K - J. Biol. Chem. (2008)

Proposed model for the expression of acrA and acrB multidrug efflux genes by RamA. In one pathway, bile may bind to the RamA protein, which is then converted from a low to a high activity state. In the other path, indole may activate ramA transcription to directly induce acrA and acrB.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2527123&req=5

fig11: Proposed model for the expression of acrA and acrB multidrug efflux genes by RamA. In one pathway, bile may bind to the RamA protein, which is then converted from a low to a high activity state. In the other path, indole may activate ramA transcription to directly induce acrA and acrB.
Mentions: We also suggest the existence of a different induction mechanism for acrAB via the RamA regulator (Fig. 11). Indole was shown to induce ramA expression (Fig. 9), and such an increased expression of ramA can induce acrAB (Fig. 6A). On the other hand, bile did not affect expression of ramA (Fig. 9), but it did bind to RamA (Fig. 11). This is reminiscent of the binding of bile to the Rob protein involved in regulation of acrAB in E. coli (31). We also suggest that the N-terminal domain of RamA may be required for binding of bile because cholic acid did not bind to the truncated RamA (Fig. 10). Our results suggest a mechanism in which RamA can change between an “activated state” and an “overexpressed state” in response to environmental signals, thereby inducing the AcrAB-TolC system (Fig. 11). Thus, RamA can be converted from a low activity state to a high activity state in response to bile. We also suggest that Salmonella may have an additional sensor for indole that controls ramA expression (Fig. 11).

Bottom Line: Among these pumps, AcrAB is effective in generating drug resistance and has wide substrate specificity.Other regulators of acrAB such as MarA, SoxS, Rob, SdiA, and AcrR did not contribute to acrAB induction by indole in Salmonella.Our results suggest that RamA controls the Salmonella AcrAB-TolC multidrug efflux system through dual regulatory modes in response to environmental signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.

ABSTRACT
Salmonella enterica serovar Typhimurium has at least nine multidrug efflux pumps. Among these pumps, AcrAB is effective in generating drug resistance and has wide substrate specificity. Here we report that indole, bile, and an Escherichia coli conditioned medium induced the AcrAB pump in Salmonella through a specific regulator, RamA. The RamA-binding sites were located in the upstream regions of acrAB and tolC. RamA was required for indole induction of acrAB. Other regulators of acrAB such as MarA, SoxS, Rob, SdiA, and AcrR did not contribute to acrAB induction by indole in Salmonella. Indole activated ramA transcription, and overproduction of RamA caused increased acrAB expression. In contrast, induction of ramA was not required for induction of acrAB by bile. Cholic acid binds to RamA, and we suggest that bile acts by altering pre-existing RamA. This points to two different AcrAB regulatory modes through RamA. Our results suggest that RamA controls the Salmonella AcrAB-TolC multidrug efflux system through dual regulatory modes in response to environmental signals.

Show MeSH
Related in: MedlinePlus