Mupirocin

Mupirocin is used as a topical treatment for bacterial skin infections (for example, boils, impetigo, or open wounds), which are typically due to infection by Staphylococcus aureus or Streptococcus pyogenes. It is also useful in the treatment of superficial methicillin-resistant Staphylococcus aureus (MRSA) infections. Mupirocin is inactive for most anaerobic bacteria, mycobacteria, mycoplasma, chlamydia, yeast, and fungi. Intranasal mupirocin before surgery is effective for prevention of post-operative wound infection with Staphylcoccus aureus and preventative intranasal or catheter-site treatment is effective for reducing the risk of catheter site infection in persons treated with chronic peritoneal dialysis. Resistance Shortly after the clinical use of mupirocin began, strains of Staphylococcus aureus that were resistant to mupirocin emerged, with nares clearance rates of less than 30% success. Two distinct populations of mupirocin-resistant S. aureus were isolated. One strain possessed low-level resistance (MuL: MIC = 8–256 mg/L), and another possessed high-level resistance (MuH: MIC > 256 mg/L). MuH is linked to the acquisition of a separate Ile synthetase gene, MupA. Mupirocin is not a viable antibiotic against MuH strains. Other antibiotic agents, such as azelaic acid, nitrofurazone, silver sulfadiazine, and ramoplanin, have been shown to be effective against MuH strains. Most strains of Pseudomonas fluorescens are also resistant to mupirocin as they produce the antibiotic and it's possible other species of Pseudomonas may be resistant as well. The mechanism of action of mupirocin differs from other clinical antibiotics, rendering cross-resistance to other antibiotics unlikely. ==Mechanism of action==

Pseudomonic acid (mupirocin) inhibits isoleucine—tRNA ligase in bacteria, The combined inhibition of protein synthesis and RNA synthesis results in bacteriostasis. This mechanism of action is shared with furanomycin, an analog of isoleucine. Inhibition of the tRNA ligase/synthase is brought by the structural similarity between the molecule's monic acid "head" part and isoleucyl-adenylate (Ile-AMS). The unique 9-hydroxynonanoic acid "tail" wraps around the enzyme and further stabilizes the complex, keeping the catalytic part stuck. Mupirocin is able to bind to bacterial and archaeal versions of the enzyme, but not eukaryotic versions. ==Biosynthesis==

, AT=acyl transferase, DH=dehydratase, ER=enoyl reductase, HMG=3-hydroxy-3-methylglutaric acid, MeT=methyl transferase, KR=ketoreductase, KS=ketosynthase, TE=thioesterase. of monic acid is attached to C3 by the following reaction scheme. MupH is a Hydroxymethylglutaryl-Coenzyme A synthase, MupJ and MupK are Enoyl-CoA hydratases. pseudomonic acid C with a double bond between C10 and C11, instead of the epoxide of PA-A, and pseudomonic acid D with a double bond at C4' and C5' in the 9-hydroxy-nonanoic acid portion of mupirocin. Biosynthesis of pseudomonic acid A The 74 kb mupirocin gene cluster contains six multi-domain enzymes and twenty-six other peptides (Table 1). Four large multi-domain type I polyketide synthase (PKS) proteins are encoded, as well as several single function enzymes with sequence similarity to type II PKSs. Monic acid biosynthesis Biosynthesis of the 17C monic acid unit begins on MmpD (Figure 1). Gene knockout experiments of mupO, mupU, mupV, and macpE have eliminated PA-A production. It is proposed that MmpB to catalyze the synthesis of 9-HN (Figure 5). MmpB contains a KS, KR, DH, 3 ACPs, and a thioesterase (TE) domain. It does not contain an enoyl reductase (ER) domain, which would be required for the complete reduction to the nine-carbon fatty acid. MupE is a single-domain protein that shows sequence similarity to known ER domains and may complete the reaction. == References ==