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Transcriptome analysis of responses to rhodomyrtone in methicillin-resistant Staphylococcus aureus.

ABSTRACT: Rhodomyrtone, purified from Rhodomyrtus tomentosa (Aiton) Hassk, exhibits a high degree of potency against methicillin-resistant Staphylococcus aureus (MRSA). We recently demonstrated that exposure of MRSA to a subinhibitory concentration (0.174 µg/ml) of rhodomyrtone resulted in the alteration of expression of several functional classes of bacterial proteins. To provide further insight into the antibacterial mode of action of this compound, we determined the impact of exposure to rhodomyrtone on the gene transcriptional profile of MRSA using microarray analysis. Exposure of MRSA to subinhibitory concentrations (0.5MIC; 0.5 µg/ml) of rhodomyrtone revealed significant modulation of gene expression, with induction of 64 genes and repression of 35 genes. Prominent changes in response to exposure to rhodomyrtone involved genes encoding proteins essential to metabolic pathways and processes such as amino acid metabolism, membrane function, ATP-binding cassette (ABC) transportation and lipoprotein and nucleotide metabolism. Genes involved in the synthesis of the aspartate family of amino acids, in particular proteins encoded by the dap operon were prominent. The diaminopimelate (DAP) biosynthetic pathway is the precursor of lysine synthesis and is essential for peptidoglycan biosynthesis. However, phenotypic analysis of the peptidoglycan amino acid content of rhodomyrtone-treated MRSA did not differ significantly from that extracted from control cells. Genes involved in the biosynthesis of amino acids and peptidoglycan, and a high affinity ATP-driven K ((+)) transport system, were investigated by quantitative reverse transcription-PCR (qRT-PCR) using EMRSA-16 1, 4, or 18 h after exposure to rhodomyrtone and in general the data concurred with that obtained by microarray, highlighting the relevance of the DAP biosynthetic pathway to the mode of action of rhodomyrtone.

SUBMITTER: Sianglum W

PROVIDER: S-EPMC3459976 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Transcriptome analysis of responses to rhodomyrtone in methicillin-resistant Staphylococcus aureus.

Sianglum Wipawadee W Srimanote Potjanee P Taylor Peter W PW Rosado Helena H Voravuthikunchai Supayang P SP

PloS one 20120927 9

Rhodomyrtone, purified from Rhodomyrtus tomentosa (Aiton) Hassk, exhibits a high degree of potency against methicillin-resistant Staphylococcus aureus (MRSA). We recently demonstrated that exposure of MRSA to a subinhibitory concentration (0.174 µg/ml) of rhodomyrtone resulted in the alteration of expression of several functional classes of bacterial proteins. To provide further insight into the antibacterial mode of action of this compound, we determined the impact of exposure to rhodomyrtone o ...[more]

PMID: 23029218

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Project description:Methicillin resistant Staphylococcus aureus (MRSA) infection is becoming refractory to existing antibiotic therapy owing to the inherent ability of S. aureus to develop rapid resistance and is considered a major threat to public health. We found that a natural isolate of Bacillus pumilus from the Columbia River Estuary produces a strong anti-MRSA compound, amicoumacin A. As amicoumacin A has been reported to exhibit anti-microbial, anti-inflammatory, and anti-ulcer activities, we sought to uncover its mechanism of action. Genome-wide transcriptome analysis of S. aureus COL in response to amicoumacin A showed alteration in the expression of genes involved in several cellular processes including cell envelope turnover, cross-membrane transport, virulence, metabolism, and general stress response. The most highly induced gene was lrgA, encoding an antiholin-like product, which has been shown to be induced in response to a collapse of membrane potential. In order to gain further insight into the mechanism of action of amicoumacin A, a whole genome comparison of wild-type COL and amicoumacin A-resistant mutants isolated by serial passage method was carried out. Single point mutations resulting in codon substitutions were uncovered in several distinct genes: ksgA, RNA dimethyltranferase; fusA, elongation factor G; dnaG, primase, ; lacD, tagatose 1,6-bisphosphate aldolase, ; and SACOL0611, encoding a putative glycosyl transferase gene. Based on these results, a candidate approach was undertaken to recreate the same amino acid substitution individually in FusA and KsgA, each of which resulted in two-fold resistance towards amicoumacin A. The fusA gene is known as the site for fusidic acid- resistant mutations; however the codon substitutions in EF-G that cause amicoumacin A resistance and fusidic acid resistance occur in separate domains and do not bring about cross resistance. Taken together, these results suggest that amicoumacin A might cause perturbation of the cell membrane and lead to energy dissipation. Decreased rates of cellular metabolism including protein synthesis and DNA replication in resistant strains might allow cells to compensate for membrane dysfunction and thus increase cell survivability.

Dataset Information

Transcriptome analysis of responses to rhodomyrtone in methicillin-resistant Staphylococcus aureus.

Publications

Transcriptome analysis of responses to rhodomyrtone in methicillin-resistant Staphylococcus aureus.

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