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Serratia marcescens RamA Expression Is under PhoP-Dependent Control and Modulates Lipid A-Related Gene Transcription and Antibiotic Resistance Phenotypes.

ABSTRACT: Serratia marcescens is an enteric bacterium that can function as an opportunistic pathogen with increasing incidence in clinical settings. This is mainly due to the ability to express a wide range of virulence factors and the acquisition of antibiotic resistance mechanisms. For these reasons, S. marcescens has been declared by the World Health Organization (WHO) as a research priority to develop alternative antimicrobial strategies. In this study, we found a PhoP-binding motif in the promoter region of transcriptional regulator RamA of S. marcescens RM66262. We demonstrated that the expression of ramA is autoregulated and that ramA is also part of the PhoP/PhoQ regulon. We have also shown that PhoP binds directly and specifically to ramA, mgtE1, mgtE2, lpxO1, and lpxO2 promoter regions and that RamA binds to ramA and lpxO1 but not to mgtE1 and lpxO2, suggesting an indirect control for the latter genes. Finally, we have demonstrated that in S. marcescens, RamA overexpression induces the AcrAB-TolC efflux pump, required to reduce the susceptibility of the bacteria to tetracycline and nalidixic acid. In sum, we here provide the first report describing the regulation of ramA under the control of the PhoP/PhoQ regulon and the regulatory role of RamA in S. marcescens. IMPORTANCE We demonstrate that in S. marcescens, the transcriptional regulator RamA is autoregulated and also controlled by the PhoP/PhoQ signal transduction system. We show that PhoP is able to directly and specifically bind to ramA, mgtE1, mgtE2, lpxO1, and lpxO2 promoter regions. In addition, RamA is able to directly interact with the promoter regions of ramA and lpxO1 but indirectly regulates mgtE1 and lpxO2. Finally, we found that in S. marcescens, RamA overexpression induces the AcrAB-TolC efflux pump, required to reduce susceptibility to tetracycline and nalidixic acid. Collectively, these results further our understanding of the PhoP/PhoQ regulon in S. marcescens and demonstrate the involvement of RamA in the protection against antibiotic challenges.

SUBMITTER: Mariscotti JF

PROVIDER: S-EPMC8316080 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sulfur is an essential nutrient that contributes to cellular redox homeostasis, transcriptional regulation, and translation initiation when incorporated into different biomolecules. Transport and reduction of extracellular sulfate followed by cysteine biosynthesis is a major pathway of bacterial sulfur assimilation. For the opportunistic pathogen Serratia marcescens, function of the cysteine biosynthesis pathway is required for extracellular phospholipase activity and flagellum-mediated surface motility, but little else is known about the influence of sulfur assimilation on the physiology of this organism. In this work, it was determined that an S. marcescens cysteine auxotroph fails to differentiate into hyperflagellated and elongated swarmer cells and that cysteine, but not other organic sulfur molecules, restores swarming motility to these bacteria. The S. marcescens cysteine auxotroph further exhibits reduced transcription of phospholipase, hemolysin, and flagellin genes, each of which is subject to transcriptional control by the flagellar regulatory system. Based on these data and the central role of cysteine in sulfur assimilation, it was reasoned that environmental sulfur availability may contribute to the regulation of these functions in S. marcescens Indeed, bacteria that are starved for sulfate exhibit substantially reduced transcription of the genes for hemolysin, phospholipase, and the FlhD flagellar master regulator. A global transcriptomic analysis further defined a large set of S. marcescens genes that are responsive to extracellular sulfate availability, including genes that encode membrane transport, nutrient utilization, and metabolism functions. Finally, sulfate availability was demonstrated to alter S. marcescens cytolytic activity, suggesting that sulfate assimilation may impact the virulence of this organism.IMPORTANCESerratia marcescens is a versatile bacterial species that inhabits diverse environmental niches and is capable of pathogenic interactions with host organisms ranging from insects to humans. This report demonstrates for the first time the extensive impacts that environmental sulfate availability and cysteine biosynthesis have on the transcriptome of S. marcescens The finding that greater than 1,000 S. marcescens genes are differentially expressed depending on sulfate availability suggests that sulfur abundance is a crucial factor that controls the physiology of this organism. Furthermore, the high relative expression levels for the putative virulence factors flagella, phospholipase, and hemolysin in the presence of sulfate suggests that a sulfur-rich host environment could contribute to the transcription of these genes during infection.

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Serratia marcescens RamA Expression Is under PhoP-Dependent Control and Modulates Lipid A-Related Gene Transcription and Antibiotic Resistance Phenotypes.

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