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Binding of the gene repressor BlaI to the bla operon in methicillin-resistant Staphylococcus aureus.

ABSTRACT: The expression of the gene products in many methicillin-resistant Staphylococcus aureus (MRSA) strains is regulated by the gene repressor BlaI. Here we show that BlaI is a mixture of monomer and dimer at in vivo concentrations, binds to the operator regions preferentially as a monomeric protein, and the measured dissociation constants and in vivo concentrations account for the basal level transcription of the resistance genes. These observations for the first time provide a quantitative picture of the processes that take place in the cytoplasm that lead to the induction of antibiotic resistance factors to counter the challenge by ?-lactams.

SUBMITTER: Llarrull LI

PROVIDER: S-EPMC2942778 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Binding of the gene repressor BlaI to the bla operon in methicillin-resistant Staphylococcus aureus.

Llarrull Leticia I LI Prorok Mary M Mobashery Shahriar S

Biochemistry 20100901 37

The expression of the gene products in many methicillin-resistant Staphylococcus aureus (MRSA) strains is regulated by the gene repressor BlaI. Here we show that BlaI is a mixture of monomer and dimer at in vivo concentrations, binds to the operator regions preferentially as a monomeric protein, and the measured dissociation constants and in vivo concentrations account for the basal level transcription of the resistance genes. These observations for the first time provide a quantitative picture ...[more]

PMID: 20722402

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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

Binding of the gene repressor BlaI to the bla operon in methicillin-resistant Staphylococcus aureus.

Publications

Binding of the gene repressor BlaI to the bla operon in methicillin-resistant Staphylococcus aureus.

Similar Datasets

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