Dataset Information

GlmM operon and methicillin-resistant glmM suppressor mutants in Staphylococcus aureus.

ABSTRACT: The Staphylococcus aureus phosphoglucosamine mutase gene glmM was shown to be the last gene of a three-cistron operon, orf1-orf2-glmM. One transcriptional start was identified upstream of orf1, and a second start producing a monocistronic transcript was identified upstream of glmM. Disruption of glmM abolished GlmM production, decreased methicillin resistance, and resulted in teicoplanin hypersusceptibility without affecting the production of the endogenous penicillin-binding proteins and PBP 2'. Complementation of the glmM mutation by the complete glmM operon restored both methicillin resistance and normal teicoplanin susceptibility. In contrast, a highly methicillin-resistant suppressor mutant obtained by selection for growth in the presence of methicillin remained GlmM deficient and teicoplanin hypersusceptible. The suppressor mutation was not linked to the glmM operon but was correlated with decreased autolysis and increased production of a 49-kDa protein, suggesting that there is an alternative pathway for glucosamine-1-phosphate synthesis in S. aureus.

SUBMITTER: Glanzmann P

PROVIDER: S-EPMC89057 | biostudies-literature | 1999 Feb

REPOSITORIES: biostudies-literature

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glmM operon and methicillin-resistant glmM suppressor mutants in Staphylococcus aureus.

Glanzmann P P Gustafson J J Komatsuzawa H H Ohta K K Berger-Bächi B B

Antimicrobial agents and chemotherapy 19990201 2

The Staphylococcus aureus phosphoglucosamine mutase gene glmM was shown to be the last gene of a three-cistron operon, orf1-orf2-glmM. One transcriptional start was identified upstream of orf1, and a second start producing a monocistronic transcript was identified upstream of glmM. Disruption of glmM abolished GlmM production, decreased methicillin resistance, and resulted in teicoplanin hypersusceptibility without affecting the production of the endogenous penicillin-binding proteins and PBP 2' ...[more]

PMID: 9925512

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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

GlmM operon and methicillin-resistant glmM suppressor mutants in Staphylococcus aureus.

Publications

glmM operon and methicillin-resistant glmM suppressor mutants in Staphylococcus aureus.

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