Dataset Information

Activation of BlaR1 protein of methicillin-resistant Staphylococcus aureus, its proteolytic processing, and recovery from induction of resistance.

ABSTRACT: The fates of BlaI, the gene repressor protein for the bla operon, BlaR1, the ?-lactam sensor/signal transducer, and PC1 ?-lactamase in four strains of Staphylococcus aureus upon exposure to four different ?-lactam antibiotics were investigated as a function of time. The genes for the three proteins are encoded by the bla operon, the functions of which afford inducible resistance to ?-lactam antibiotics in S. aureus. BlaR1 protein is expressed at low copy number. Acylation of the sensor domain of BlaR1 by ?-lactam antibiotics initiates signal transduction to the cytoplasmic domain, a zinc protease, which is activated and degrades BlaI. This proteolytic degradation derepresses transcription of all three genes, resulting in inducible resistance. These processes take place within minutes of exposure to the antibiotics. The BlaR1 protein was shown to undergo fragmentation in three S. aureus strains within the time frame relevant for manifestation of resistance and was below the detection threshold in the fourth. Two specific sites of fragmentation were identified, one cytoplasmic and the other in the sensor domain. This is proposed as a means for turnover, a process required for recovery from induction of resistance in S. aureus in the absence of the antibiotic challenge. In S. aureus not exposed to ?-lactam antibiotics (i.e. not acylated by antibiotic) the same fragmentation of BlaR1 is still observed, including the shedding of the sensor domain, an observation that leads to the conclusion that the sites of proteolysis might have evolved to predispose the protein to degradation within a set period of time.

SUBMITTER: Llarrull LI

PROVIDER: S-EPMC3207446 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Activation of BlaR1 protein of methicillin-resistant Staphylococcus aureus, its proteolytic processing, and recovery from induction of resistance.

Llarrull Leticia I LI Toth Marta M Champion Matthew M MM Mobashery Shahriar S

The Journal of biological chemistry 20110906 44

The fates of BlaI, the gene repressor protein for the bla operon, BlaR1, the β-lactam sensor/signal transducer, and PC1 β-lactamase in four strains of Staphylococcus aureus upon exposure to four different β-lactam antibiotics were investigated as a function of time. The genes for the three proteins are encoded by the bla operon, the functions of which afford inducible resistance to β-lactam antibiotics in S. aureus. BlaR1 protein is expressed at low copy number. Acylation of the sensor domain of ...[more]

PMID: 21896485

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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

Activation of BlaR1 protein of methicillin-resistant Staphylococcus aureus, its proteolytic processing, and recovery from induction of resistance.

Publications

Activation of BlaR1 protein of methicillin-resistant Staphylococcus aureus, its proteolytic processing, and recovery from induction of resistance.

Similar Datasets

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