Abstract
fmtA encodes a low-affinity penicillin binding protein in Staphylococcus aureus. It is part of the core cell wall stimulon and is involved in methicillin resistance in S. aureus. Here, we report that the transcription factor, SarA, a pleiotropic regulator of virulence genes in S. aureus, regulates the expression of fmtA. In vitro binding studies with purified SarA revealed that it binds to specific sites within the 541-bp promoter region of fmtA. Mutation of a key residue of the regulatory activity of SarA (Arg90) abolished binding of SarA to the fmtA promoter, suggesting that SarA binds specifically to the fmtA promoter region. In vivo analysis of the fmtA promoter using a lux operon reporter fusion show high level expression following oxacillin induction, which was abrogated in a sarA mutant strain. These data suggest that SarA is essential for the induction of fmtA expression by cell wall-specific antibiotics. Further, in vitro transcription studies show that SarA enhances fmtA transcription and suggest that regulation of fmtA could be via a SigA-dependent mechanism. Overall, our results show that SarA plays a direct role in the regulation of fmtA expression via binding to the fmtA promoter.
Highlights
Staphylococcus aureus is a versatile gram-positive pathogen capable of causing a wide range of diseases, ranging from superficial abscesses to pneumonia, endocarditis, and sepsis [1]
These beads when incubated with oxacillin-induced cell extracts pulled down several proteins that were identified by analyzing LC-MS-MS data using the MASCOT program and a probability based Mowse score of
The analyses showed the presence of staphylococcal accessory regulator A (SarA), pyruvate carboxylase, biotin carboxyl carrier protein of acetyl-CoA carboxylase, DNA-direct RNA polymerase alpha chain, DNA polymerase I, translation elongation factor Tu, translation elongation factor G, elongation factor TS, chaperone protein dnaK, chaperonin GroEL, cell division proteins FtsZ, DNA binding protein II, putative DNAbinding protein, and 30S ribosomal protein S5
Summary
Staphylococcus aureus is a versatile gram-positive pathogen capable of causing a wide range of diseases, ranging from superficial abscesses to pneumonia, endocarditis, and sepsis [1]. When penicillin was introduced in 1944, over 94% of S. aureus isolates were susceptible. By 1950, 50% of S. aureus isolates were penicillin-resistant, further demonstrating the remarkable ability of S. aureus to rapidly adapt to antibiotic pressure. In 1960, outbreaks of virulent S. aureus that were resistant to penicillin occurred in many hospitals. These could be treated successfully with methicillin and other newly available penicillinase-stable penicillins. By 1961, two years after the introduction of methicillin, methicillin-resistant Staphylococcus aureus (MRSA) had emerged. Some variants of MRSA have developed resistance to glycopeptide antibiotics, including vancomycin, which is the sole antibiotic that can still be used to successfully treat most S. aureus [9]
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