<!-- Definition and medical uses -->
Mupirocin, sold under the brand name Bactroban among others, is a topical antibiotic useful against superficial skin infections such as impetigo or folliculitis. It may also be used to get rid of methicillin-resistant S. aureus (MRSA) when present in the nose without symptoms. It works by blocking a bacterium's ability to make protein, which usually results in bacterial death. It is on the World Health Organization's List of Essential Medicines. In 2023, it was the 171st most commonly prescribed medication in the United States, with more than 2million prescriptions. It is available as a generic medication.
Medical uses
thumb|A tube of Bactroban
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
class=skin-invert-image|thumb|upright=2|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.]]
class=skin-invert-image|upright=2|thumb|Figure 2. The structure of pseudomonic acid A–D, labeled A to D, respectively
class=skin-invert-image|thumb|upright=2|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. 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.
{| class="wikitable"
|+Table 1: The biosynthetic gene cluster of mupirocin
|-
! Gene
! Function
|-
| mupA
| FMNH<sub>2</sub> dependent oxygenase
|-
| mmpA
| KS ACP KS KR ACP KS ACP ACP
|-
| mupB
| 3-oxoacyl-ACP synthase
|-
| mmpB
| KS DH KR ACP ACP ACP TE
|-
| mmpC
| AT AT
|-
| mmpD
| KS DH KR MeT ACP KS DH KR ACP KS DH KR MeT ACP KS KR ACP
|-
| mupC
| NADH/NADPH oxidoreductase
|-
| macpA
| ACP
|-
| mupD
| 3-oxoacyl-ACP reductase
|-
| mupE
|enoyl reductase
|-
| macpB
| ACP
|-
| mupF
| KR
|-
| macpC
| ACP
|-
| mupG
| 3-oxoacyl-ACP synthase I
|-
| mupH
| HMG-CoA synthase
|-
| mupJ
| enoyl-CoA hydratase
|-
| mupK
| enoyl-CoA hydratase
|-
| mmpE
| KS hydrolase
|-
| mupL
| putative hydrolase
|-
| mupM
| isoleucyl-tRNA synthase
|-
| mupN
| phosphopantetheinyl transferase
|-
| mupO
| cytochrome P450
|-
| mupP
|unknown
|-
| mupQ
| acyl-CoA synthase
|-
| mupS
| 3-oxoacyl-ACP reductase
|-
| macpD
| ACP
|-
| mmpF
| KS
|-
| macpE
| ACP
|-
| mupT
| ferredoxin dioxygenase
|-
| mupU
| acyl-CoA synthase
|-
| mupV
|oxidoreductase
|-
| mupW
|dioxygenase
|-
| mupR
| N-AHL-responsive transcriptional activator
|-
| mupX
| amidase/hydrolase
|-
| mupI
| N-AHL synthase
|}
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.