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Enhanced fatty acid synthesis by Sigma28 in stringent responses contributes to multidrug resistance and biofilm formation in Helicobacter pylori

ABSTRACT:

The metabolism of bacteria is closely associated with antibiotic resistance, yet the role of metabolism in the resistance of Helicobacter pylori remains unclear. In this study, we conducted integrated analysis using transcriptomics and non-targeted metabolomics to investigate the metabolic changes of antibiotic-treated H. pylori. The results revealed an upregulation in the expression of genes related to fatty acid biosynthesis. Inhibiting fatty acid biosynthesis significantly enhanced the sensitivity of H. pylori strains sensitive to antibiotics, artificially selected multidrug-resistant strains, and clinically multidrug-resistant strains, leading to the inability to form intact biofilms. Furthermore, we explored the reasons for the enhanced fatty acid synthesis in H. pylori under antibiotic pressure and found that antibiotic treatment induced a stringent response in H. pylori, activating the regulation of the downstream operon containing hp0560 by σ28, thereby enhancing the fatty acid synthesis pathway and consequently increasing H. pylori's tolerance to various antibiotics. In this study, we identified a novel mechanism by which H. pylori adapts to antibiotic pressure.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

SUBMITTER: JUNYUAN XUE

PROVIDER: MTBLS9981 | MetaboLights | 2024-06-26

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS9981	Other
	FILES	Other
	a_MTBLS9981_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS9981_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Project description:Pseudomonas aeruginosa is a major opportunistic pathogen causing a wide range of infections and one of the most problematic bacteria regarding antibiotic resistance, with an increasing incidence of multidrug and extensively-drug resistant strains, including resistance to last resource antibiotics such as carbapenems. Resistances are often due to complex interplays of naturally and acquired resistance mechanisms which are enhanced by its remarkably large regulatory network. Thus, the use of non-targeted shotgun methodologies such as mass spectrometry-based proteomics is crucial to understand these interplays and to reveal possible strain and species-specific novel mechanisms of antibiotic resistance. The aim of this study was to determine the proteomic response of two carbapenem-resistant and extensively-drug-resistant P. aeruginosa strains to subminimal inhibitory concentrations (sub-MICs) of meropenem. The strains belonged to high-risk clones ST235 and ST395, one carrying a class 1 integron-encoded VIM-4 metallo-β-lactamase and one carrying no acquired antibiotic resistance genes. Each strain was cultivated with three different sub-MICs of meropenem, and a quantitative shotgun proteomic approach was applied, using tandem mass tag (TMT) isobaric labeling followed by nano-liquid chromatography tandem-mass spectrometry, to determine significantly up- or down-regulated proteins and enriched groups of proteins and pathways. Cultivation of both strains with ½ and ¼ of the MIC, resulted in hundreds of differentially regulated proteins, including several β-lactamases, transport-related proteins (including multiple porins and efflux pumps), proteins associated with peptidoglycan metabolism and cell wall organization and dozens of regulatory proteins. Remarkably, all components of the H1 type VI secretion system were up-regulated in one of the strains. Enrichment analyses revealed that multiple metabolic pathways were affected. Additionally, numerous proteins of unknown function were also differentially-regulated in each strain. In conclusion, high subminimal-inhibitory concentrations of meropenem cause massive changes in the proteomes of carbapenem-resistant P. aeruginosa strains, involving a wide range of common and strain-specific mechanisms and proteins, many still uncharacterized which might potentially play a role in the susceptibility of P. aeruginosa to meropenem.

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Enhanced fatty acid synthesis by Sigma28 in stringent responses contributes to multidrug resistance and biofilm formation in Helicobacter pylori

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