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Staphylococcus aureus

ABSTRACT: Opportunistic pathogens resistant to antibiotics

PROVIDER: PRJNA865540 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR21047739_1.fastq.gz	Fastqsanger.gz
	SRR21047739_2.fastq.gz	Fastqsanger.gz
	SRR21047672_1.fastq.gz	Fastqsanger.gz
	SRR21047672_2.fastq.gz	Fastqsanger.gz

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Staphylococcus aureus nonribosomal peptide secondary metabolites regulate virulence

Project description:Staphylococcus aureus is a major human pathogen and resistant to numerous clinically used antibiotics. The first antibiotic developed for S. aureus infections was the nonribosomal petide secondary metabolite penicillin. We discovered cryptic nonribosomal peptide secondary metabolites, the aureusimines, made by S. aureus itself that are not antibiotics, but function as small molecule regulators of virulence factor expression. Using established rules and codes for nonribosomal peptide assembly we predicted these nonribosomal peptides, and used these predictions to identify them from S. aureus culture broths. Functional studies using global microarray and mouse bacteremia models established that the aureusimines control virulence factor expression and are necessary for productive infections. This is the first report of the aureusimines and has important implications for the treatment of drug resistant S. aureus. Targeting aureusimine synthesis may provide novel anti-infectives.

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Project description:The clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in multi-drug resistant bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system, and the ramifications of prolonged bacterial exposure to AMPs are not fully understood. Here we show that in vitro serial passage of a clinical USA300 methicillin-resistant Staphylococcus aureus strain in a host-mimicking environment containing host-derived AMPs results in the selection of stable AMP-resistance. AMP-resistant S. aureus mutants often displayed little to no fitness cost and caused invasive disease in mice. Further, this phenotype coincided with diminished susceptibility to both clinically prescribed antibiotics and human defense peptides. These findings suggest that therapeutic use of AMPs could select for virulent mutants with cross-resistance to human innate immunity as well as antibiotic therapy. Thus, therapeutic use of AMPs and the implications of cross-resistance need to be carefully monitored and evaluated.

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Project description:Staphylococcus aureus is a human commensal bacterium and opportunistic pathogen. Chronicity of S. aureus infection has been linked to bacterial survival within host cells including macrophages. Bacteria recovered from the intracellular milieu often form small colony variants (SCV) which are growing slowly, show reduced virulence factor production and are more resistant to antibiotics. Branched chain amino acids (BCAA) are an important class of nutrients for S. aureus. We therefore tested if components of BCAA biosynthesis or transport would alter the outcome of macrophage infection. We found that S. aureus mutants in the BCAA transporter BrnQ1 survived experimental infection of primary human macrophages for the complete duration of the 28 day experiments. Since phenotypic differences between brnQ1 mutants and wild-type bacteria occurred around 10 h p.i., we performed dual RNA-seq by which we determined the transcriptomes of both, pathogen and macrophage host, simultaneously. Our data indicate that at that time transcriptomic changes exclusively are governed by the internalized pathogen. The differential analysis of S. aureus WT and its isogenic brnQ1 mutant surprisingly demonstrated a dysregulation of iron-dependently regulated genes.

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