Mupirocin

Mupirocin, sold under the brand name Bactroban among others, is a topical antibiotic useful against superficial skin infections such as impetigo or folliculitis.

[6] Common side effects include itchiness and rash at the site of application, headache, and nausea.

[15] 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.

[17] Resistance in the MuL strains is probably due to mutations in the organism's wild-type isoleucyl-tRNA synthetase (IleS).

In E. coli IleS, a single amino acid mutation was shown to alter mupirocin resistance.

Other antibiotic agents, such as azelaic acid, nitrofurazone, silver sulfadiazine, and ramoplanin have been shown to be effective against MuH strains.

[22] Pseudomonic acid (mupirocin) inhibits isoleucine—tRNA ligase in bacteria,[14] leading to depletion of isoleucyl-tRNA and accumulation of the corresponding uncharged tRNA.

[24] 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.

The mupirocin cluster exhibits an atypical acyltransferase (AT) organization, in that there are only two AT domains, and both are found on the same protein, MmpC.

The chain is extended by malonyl-CoA, followed by a SAM-dependent methylation at C12 (see Figure 2 for PA-A numbering) and reduction of the B-keto group to an alcohol.

The dehydration (DH) domain in module 1 is predicted to be non-functional due to a mutation in the conserved active site region.

[citation needed] Assembly of monic acid is continued by the transfer of the 12C product of MmpD to MmpA.

[28] Gene knockout experiments of mupO, mupU, mupV, and macpE have eliminated PA-A production.

[27] 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.

A tube of Bactroban
Figure 1 . The domain structure of MmpA, MmpC, and MmpD for the synthesis of monic acid. The biosynthesis of monic acid is not colinear but has been rearranged in this diagram. The protein name is displayed inside of the arrow with module and domain structure listed below. ACP= acyl carrier protein , AT= acyl transferase , DH= dehydratase , ER=enoyl reductase, HMG= 3-hydroxy-3-methylglutaric acid , MeT= methyl transferase , KR=ketoreductase, KS= ketosynthase , TE= thioesterase .
Figure 2 . The structure of pseudomonic acid A–D, labeled A to D, respectively
Figure 3 . The C15 methyl group 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 . [ 27 ]
Figure 4 . The pyran ring of mupirocin is generated in this proposed multistep reaction. Gene knockouts of mupO, mupU, mupV and macpE abolish PA-A production but not PA-B production, demonstrating that PA-B is a precursor to PA-A. [ 28 ]
Figure 5 . MmpB is proposed to synthesize 9-HN with a 3-hydroxy-propionate starter unit and three malonyl-CoA extender units. The domain structure of MmpB is shown below alongside MupE, the proposed enoyl reductase required for complete saturation of 9-HN. ACP= acyl carrier protein , DH= dehydratase , ER=enoyl reductase, KR=ketoreductase, KS= ketosynthase , TE= thioesterase .