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Mupirocin, sold under the brand name Bactroban among others, is a topical antibiotic useful against superficial skin infections such as impetigo or folliculitis.<ref>Template:Cite journal</ref><ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=WHO2008>Template:Cite book</ref> It may also be used to get rid of methicillin-resistant S. aureus (MRSA) when present in the nose without symptoms.<ref name=AHFS2016/> Due to concerns of developing resistance, use for greater than ten days is not recommended.<ref name=WHO2008/> It is used as a cream or ointment applied to the skin.<ref name=AHFS2016/>
Common side effects include itchiness and rash at the site of application, headache, and nausea.<ref name=AHFS2016/> Long-term use may result in increased growth of fungi.<ref name=AHFS2016/> Use during pregnancy and breastfeeding appears to be safe.<ref name=AHFS2016/> Mupirocin is chemically a carboxylic acid.<ref>Template:Cite book</ref> It works by blocking a bacteria's ability to make protein, which usually results in bacterial death.<ref name=AHFS2016/>
Mupirocin was initially isolated in 1971 from Pseudomonas fluorescens.<ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> In 2022, it was the 162nd most commonly prescribed medication in the United States, with more than 3Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is available as a generic medication.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Medical usesEdit
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.<ref name="pmid365175">Template:Cite journal</ref> Mupirocin is inactive for most anaerobic bacteria, mycobacteria, mycoplasma, chlamydia, yeast, and fungi.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref>Template:Cite journal</ref>
ResistanceEdit
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.<ref name="pmid9511032">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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).<ref name="pmid9511032"/> 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.<ref name="pmid7929087">Template:Cite journal</ref> MuH is linked to the acquisition of a separate Ile synthetase gene, MupA.<ref name="pmid8431015">Template:Cite journal</ref> 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.<ref name="pmid9511032"/>
Most strains of Cutibacterium acnes, a causative agent in the skin disease acne vulgaris, are naturally resistant to mupirocin.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.Template:Citation needed
The mechanism of action of mupirocin differs from other clinical antibiotics, rendering cross-resistance to other antibiotics unlikely.<ref name="pmid9511032"/> However, the MupA gene may co-transfer with other antibacterial resistance genes. This has been observed already with resistance genes for triclosan, tetracycline, and trimethoprim.<ref name="pmid9511032"/> It may also result in overgrowth of non-susceptible organisms.Template:Citation needed
A second type of high-level resistant synthetase was discovered in 2012 and termed MupB. It was found in a Canadian MRSA isolate "MUP87" and is probably located on a nonconjugative plasmid.<ref>Template:Cite journal</ref>
Mechanism of actionEdit
Pseudomonic acid (mupirocin) inhibits isoleucine—tRNA ligase in bacteria,<ref name="pmid365175"/> leading to depletion of isoleucyl-tRNA and accumulation of the corresponding uncharged tRNA. Depletion of isoleucyl-tRNA results in inhibition of protein synthesis. The uncharged form of the tRNA binds to the aminoacyl-tRNA binding site of ribosomes, triggering the formation of (p)ppGpp, which in turn inhibits RNA synthesis.<ref name="pmid4576025">Template:Cite journal</ref> The combined inhibition of protein synthesis and RNA synthesis results in bacteriostasis. This mechanism of action is shared with furanomycin, an analog of isoleucine.<ref name="pmid4982424">Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref> Mupirocin is able to bind to bacterial and archaeal versions of the enzyme, but not eukaryotic versions.<ref>Template:Cite journal</ref>
BiosynthesisEdit
Mupirocin is a mixture of several pseudomonic acids, with pseudomonic acid A (PA-A) constituting greater than 90% of the mixture. Also present in mupirocin are pseudomonic acid B with an additional hydroxyl group at C8,<ref name="pmid402373">Template:Cite journal</ref> pseudomonic acid C with a double bond between C10 and C11, instead of the epoxide of PA-A,<ref name="urlScienceDirect - Tetrahedron Letters: The structure and configuration of pseudomonic acid C">Template:Cite journal</ref> and pseudomonic acid D with a double bond at C4` and C5` in the 9-hydroxy-nonanoic acid portion of mupirocin.<ref>Template:Cite journal</ref>
Biosynthesis of pseudomonic acid AEdit
The 74 kb mupirocin gene cluster contains six multi-domain enzymes and twenty-six other peptides (Table 1).<ref name="pmid12770824">Template:Cite journal</ref> 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.<ref name="pmid12770824"/> Therefore, it is believed that mupirocin is constructed by a mixed type I and type II PKS system. 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. These AT domains are the only domains present on MmpC, while the other three type I PKS proteins contain no AT domains.<ref name="pmid12770824"/> The mupirocin pathway also contains several tandem acyl carrier protein doublets or triplets. This may be an adaptation to increase the throughput rate or to bind multiple substrates simultaneously.<ref name="pmid12770824"/>
Pseudomonic acid A is the product of an esterification between the 17C polyketide monic acid and the 9C fatty acid 9-hydroxy-nonanoic acid. The possibility that the entire molecule is assembled as a single polyketide with a Baeyer-Villiger oxidation inserting an oxygen into the carbon backbone has been ruled out because C1 of monic acid and C9' of 9-hydroxy-nonanoic acid are both derived from C1 of acetate.<ref name="pmid402372">Template:Cite journal</ref>
| Gene | Function |
|---|---|
| mupA | FMNH2 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 biosynthesisEdit
Biosynthesis of the 17C monic acid unit begins on MmpD (Figure 1).<ref name="pmid12770824"/> One of the AT domains from MmpC may transfer an activated acetyl group from acetyl-Coenzyme A (CoA) to the first ACP domain. 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. Module 2 adds another two carbons by the malonyl-CoA extender unit, followed by ketoreduction (KR) and dehydration. Module three adds a malonyl-CoA extender unit, followed by SAM-dependent methylation at C8, ketoreduction, and dehydration. Module 4 extends the molecule with a malonyl-CoA unit followed by ketoreduction.Template:Citation needed
Assembly of monic acid is continued by the transfer of the 12C product of MmpD to MmpA.<ref name="pmid12770824"/>
Post-PKS tailoringEdit
The keto group at C3 is replaced with a methyl group in a multi-step reaction (Figure 3). MupG begins by decarboxylating a malonyl-ACP. The alpha carbon of the resulting acetyl-ACP is linked to C3 of the polyketide chain by MupH. This intermediate is dehydrated and decarboxylated by MupJ and MupK, respectively.<ref name="pmid12770824"/>
The formation of the pyran ring requires many enzyme-mediated steps (Figure 4). The double bond between C8 and C9 is proposed to migrate to between C8 and C16.<ref name="pmid16039529">Template:Cite journal</ref> Gene knockout experiments of mupO, mupU, mupV, and macpE have eliminated PA-A production.<ref name="pmid16039529"/> PA-B production is not removed by these knockouts, demonstrating that PA-B is not created by hydroxylating PA-A. A knockout of mupW eliminated the pyran ring, identifying MupW as being involved in ring formation.<ref name="pmid16039529"/>
The epoxide of PA-A at C10-11 is believed to be inserted after pyran formation by a cytochrome P450 such as MupO.<ref name="pmid12770824"/> A gene knockout of mupO abolished PA-A production but PA-B, which also contains the C10-C11 epoxide, remained.<ref name="pmid16039529"/>
9-Hydroxy-nonanoic acid biosynthesisEdit
The nine-carbon fatty acid 9-hydroxy-nonanoic acid (9-HN) is derived as a separate compound and later esterified to monic acid to form pseudomonic acid. 13C labeled acetate feeding has shown that C1-C6 are constructed with acetate in the canonical fashion of fatty acid synthesis. C7' shows only C1 labeling of acetate, while C8' and C9' show a reversed pattern of 13C labeled acetate.<ref name="pmid402372"/> It is speculated that C7-C9 arises from a 3-hydroxypropionate starter unit, which is extended three times with malonyl-CoA and fully reduced to yield 9-HN. It has also been suggested that 9-HN is initiated by 3-hydroxy-3-methylglutaric acid (HMG). This latter theory was not supported by feeding of [3-14C] or [3,6-13C2]-HMG.<ref>Template:Cite journal</ref>
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.<ref name="pmid12770824"/> 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.<ref name="pmid12770824"/>
ReferencesEdit
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