On the mode of action of pseudomonic acid: Inhibition of protein synthesis in Staphylococcus aureus.

Abstract

The effect of the antibiotic, pseudomonic acid, on the major metabolic processes in Staphylococcus aureus was studied. The primary effect of low concentrations of the antibiotic, leading to bacteriostasis, is inhibition of protein synthesis. Pseudomonic acid also severely inhibits RNA synthesis which can be prevented by chloramphenicol treatment. DNA and cell wall peptidoglycan synthesis are inhibited to a lesser extent and interference with these processes is considered to be a secondary effect. Oxidative phosphorylation as measured by ATP levels was not inhibited.

Occurrence of the regulatory nucleotides ppGpp and pppGpp following induction of the stringent response in staphylococci

“…In the presence of mupirocin, RNA synthesis in E. coli and S. aureus is also inhibited as a consequence of the stringent response; however, this inhibition can be reversed by chloramphenicol (15), which in E. coli, binds close to the binding site for the terminal CCA of aminoacyl tRNA in the peptidyl transferase A site (23) and reduces the amount of RelA-dependent (p)ppGpp synthesis (8,10). A stringent response mediated by (p)ppGpp has been detected in some gram-positive and gram-negative bacteria and higher organisms after amino acid starvation or induction by a variety of antibiotics (7,18,26).…”

Development and validation of a liquid chromatographic method for in vitro mupirocin quantification in both skin layers and percutaneous penetration studies

“…Mupirocin was found to inhibit bacterial isoleucyl-tRNA synthetase [3,4], blocking protein synthesis and indirectly inhibiting RNA synthesis [5]. The last part of the epoxy chain presents a structural analogy with isoleucyn and it interacts reversible and specifically with the aminoacid at the active site of the enzyme.…”

A continuous assay for monitoring the synthetic and proofreading activities of multiple aminoacyl-tRNA synthetases for high-throughput drug discovery

“…Mupirocin (pseudomonic acid), naturally produced by Pseudomonas fluorescens , is a broad-spectrum competitive inhibitor that blocks the synthetic site of various bacterial IleRSs, but not that of the human enzyme [7,8]. This compound is currently used as a topical ointment to treat various skin infections including impetigo and methicillin-resistant Staphylococcus aureus (MRSA) [9-11]. The compound AN2690, developed by Anacor for the topical treatment of onychomycosis, binds the proofreading site of fungal LeuRS.…”