Abstract
The Salmonella enterica serovar Typhimurium PhoP/PhoQ system has largely been studied as a paradigmatic two-component regulatory system not only to dissect structural and functional aspects of signal transduction in bacteria but also to gain knowledge about the versatile devices that have evolved allowing a pathogenic bacterium to adjust to or counteract environmental stressful conditions along its life cycle. Mg(2+) limitation, acidic pH, and the presence of cationic antimicrobial peptides have been identified as cues that the sensor protein PhoQ can monitor to reprogram Salmonella gene expression to cope with extra- or intracellular challenging conditions. In this work, we show for the first time that long chain unsaturated free fatty acids (LCUFAs) present in Salmonella growth medium are signals specifically detected by PhoQ. We demonstrate that LCUFAs inhibit PhoQ autokinase activity, turning off the expression of the PhoP-dependent regulon. We also show that LCUFAs exert their action independently of their cellular uptake and metabolic utilization by means of the β-oxidative pathway. Our findings put forth the complexity of input signals that can converge to finely tune the activity of the PhoP/PhoQ system. In addition, they provide a new potential biochemical platform for the development of antibacterial strategies to fight against Salmonella infections.
Highlights
The PhoP/PhoQ system governs crucial Salmonella typhimurium pathogenic traits
Plant Extracts with PhoP/PhoQ System Inhibitory Action— We performed a systematic screen from four plant extracts in a search for compounds that could modulate the activity of the PhoP/PhoQ system in Salmonella
Identical results were obtained when other PhoP-activated genes were assayed in the same fad backgrounds. Despite this last observation, which will be further examined, our results indicate that the inhibition of PhoP-activated genes by C18:2 does not require the integrity of the unsaturated fatty acid -oxidative pathway. These results show that long chain unsaturated free fatty acids (LCUFAs) present in the bacterial growth medium exert a repressive action on the PhoP/PhoQ system activity that is independent of the metabolic degradative fate of these compounds in the cell and rule out the potential involvement of an accumulation of acetylCoA or of an intermediate metabolite of the -oxidative pathway as responsible for the observed inhibition of PhoP-activated gene expression by LCUFAs
Summary
The PhoP/PhoQ system governs crucial Salmonella typhimurium pathogenic traits. Results: A screening of natural compounds showed that long chain fatty acids present in the bacterial growth medium downregulate the PhoP/PhoQ-dependent regulon. We carried out a screening of extracts from native plant species to identify naturally occurring molecules that would modulate PhoP/PhoQ activity This search led us to determine that long chain unsaturated fatty acids (LCUFAs) constitute specific input signals that downregulate the PhoP/PhoQ system activity. We demonstrate that this repression is due to the inhibition of PhoQ autophosphorylation capacity. Our results indicate that free unsaturated fatty acids constitute specific signals detected by PhoQ, which provoke the inhibition of the sensor autokinase activity This effect is transmitted downstream, resulting in the inactivation of the regulator PhoP with a concomitant down-regulation of PhoPactivated gene expression. The fact that exogenously provided LCUFAs are able to signal on PhoQ widens the array of potential environmental scenarios that Salmonella is capable of perceiving in vivo in order to orchestrate the expression of virulence phenotypes by means of the PhoP/PhoQ system, and provides a rationale for the future design of new targeted antibacterial strategies
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