 | |
 Pseudomonic acid A (PA-A), the principal component of mupirocin | |
| Clinical data | |
|---|---|
| Trade names | Bactroban, others |
| Other names | muciprocin[1] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a688004 |
| License data | |
| Pregnancy category |
|
| Routes of administration | Topical |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | 97% |
| Eliminationhalf-life | 20 to 40 minutes |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.106.215 |
| Chemical and physical data | |
| Formula | C26H44O9 |
| Molar mass | 500.629 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 77 to 78 °C (171 to 172 °F) |
| |
| |
 N Y (what is this?) (verify) | |
Mupirocin, sold under the brand nameBactroban among others, is a topicalantibiotic useful against superficialskin infections such asimpetigo orfolliculitis.[5][6][7] It may also be used to get rid ofmethicillin-resistantS. aureus (MRSA) when present in the nose without symptoms.[6] Due to concerns of developingresistance, use for greater than ten days is not recommended.[7] It is used as a cream or ointment applied to the skin.[6]
Common side effects include itchiness and rash at the site of application, headache, and nausea.[6] Long-term use may result in increased growth offungi.[6] Use duringpregnancy andbreastfeeding appears to be safe.[6] Mupirocin is chemically acarboxylic acid.[8] It works by blocking a bacteria's ability to make protein, which usually results inbacterial death.[6]
Mupirocin was initially isolated in 1971 fromPseudomonas fluorescens.[9] It is on theWorld Health Organization's List of Essential Medicines.[10] In 2023, it was the 171st most commonly prescribed medication in the United States, with more than 2 million prescriptions.[11][12] It is available as ageneric medication.[13]
Mupirocin is used as a topical treatment for bacterial skin infections (for example,boils,impetigo, or open wounds), which are typically due to infection byStaphylococcus aureus orStreptococcus pyogenes. It is also useful in the treatment of superficialmethicillin-resistantStaphylococcus aureus (MRSA) infections.[14] Mupirocin is inactive for most anaerobic bacteria, mycobacteria, mycoplasma, chlamydia, yeast, and fungi.[15]
Intranasal mupirocin before surgery is effective for prevention of post-operative wound infection withStaphylcoccus 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.[16]
Shortly after the clinical use of mupirocin began, strains ofStaphylococcus aureus that wereresistant to mupirocin emerged, withnares clearance rates of less than 30% success.[17][18] Two distinct populations of mupirocin-resistantS. 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).[17] Resistance in the MuL strains is probably due tomutations in the organism'swild-typeisoleucyl-tRNA synthetase (IleS). InE. coliIleS, a single amino acid mutation was shown to alter mupirocin resistance.[19] MuH is linked to the acquisition of a separate Ile synthetase gene,MupA.[20] Mupirocin is not a viable antibiotic against MuH strains. Other antibiotic agents, such asazelaic acid,nitrofurazone,silver sulfadiazine, andramoplanin, have been shown to be effective against MuH strains.[17]
Most strains ofCutibacterium acnes, a causative agent in the skin diseaseacne vulgaris, are naturally resistant to mupirocin.[21]
Most strains ofPseudomonas fluorescens are also resistant to mupirocin as they produce the antibiotic and it's possible other species ofPseudomonas may be resistant as well.[citation needed]
The mechanism of action of mupirocin differs from other clinical antibiotics, renderingcross-resistance to other antibiotics unlikely.[17] However, the MupA gene mayco-transfer with other antibacterial resistance genes. This has been observed already with resistance genes fortriclosan,tetracycline, andtrimethoprim.[17] It may also result in overgrowth of non-susceptible organisms.[citation needed]
A second type of high-level resistant synthetase was discovered in 2012 and termedMupB. It was found in a CanadianMRSA isolate "MUP87" and is probably located on a nonconjugative plasmid.[22]
Pseudomonic acid (mupirocin) inhibitsisoleucine—tRNA ligase in bacteria,[14] leading to depletion of isoleucyl-tRNA and accumulation of the correspondinguncharged tRNA. Depletion of isoleucyl-tRNA results ininhibition 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.[23] The combined inhibition of protein synthesis and RNA synthesis results in bacteriostasis. This mechanism of action is shared withfuranomycin, ananalog of isoleucine.[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.[25] Mupirocin is able to bind to bacterial and archaeal versions of the enzyme, but not eukaryotic versions.[26]
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 additionalhydroxyl group at C8,[29] pseudomonic acid C with adouble bond between C10 and C11, instead of theepoxide of PA-A,[30] and pseudomonic acid D with a double bond at C4` and C5` in the 9-hydroxy-nonanoic acid portion of mupirocin.[31]
The 74kb mupirocingene cluster contains sixmulti-domainenzymes and twenty-six otherpeptides (Table 1).[27] Four large multi-domain type Ipolyketide synthase (PKS) proteins are encoded, as well as several single function enzymes with sequence similarity to type II PKSs.[27] Therefore, it is believed that mupirocin is constructed by a mixed type I and type II PKS system. The mupirocin cluster exhibits an atypicalacyltransferase (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.[27] The mupirocin pathway also contains several tandemacyl carrier protein doublets or triplets. This may be an adaptation to increase the throughput rate or to bind multiple substrates simultaneously.[27]
Pseudomonic acid A is the product of anesterification between the 17C polyketide monic acid and the 9Cfatty acid 9-hydroxy-nonanoic acid. The possibility that the entire molecule is assembled as a single polyketide with aBaeyer-Villigeroxidation inserting anoxygen 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.[32]
| Gene | Function |
|---|---|
| mupA | FMNH2 dependent oxygenase |
| mmpA | KSACP KSKR ACP KS ACP ACP |
| mupB | 3-oxoacyl-ACP synthase |
| mmpB | KSDH KR ACP ACP ACPTE |
| mmpC | AT AT |
| mmpD | KS DH KRMeT 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 | KShydrolase |
| 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-responsivetranscriptional activator |
| mupX | amidase/hydrolase |
| mupI | N-AHL synthase |
Biosynthesis of the 17C monic acid unit begins on MmpD (Figure 1).[27] 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-dependentmethylation 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 theconservedactive 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.[citation needed]
Assembly of monic acid is continued by the transfer of the 12C product of MmpD to MmpA.[27]
The keto group at C3 is replaced with a methyl group in a multi-step reaction (Figure 3). MupG begins bydecarboxylating a malonyl-ACP. Thealpha 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.[27]
The formation of thepyran ring requires many enzyme-mediated steps (Figure 4). The double bond between C8 and C9 is proposed to migrate to between C8 and C16.[28]Gene knockout experiments of mupO, mupU, mupV, and macpE have eliminated PA-A production.[28] 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.[28]
Theepoxide of PA-A at C10-11 is believed to be inserted after pyran formation by acytochrome P450 such as MupO.[27] A gene knockout of mupO abolished PA-A production but PA-B, which also contains the C10-C11 epoxide, remained.[28]
The nine-carbonfatty acid9-hydroxy-nonanoic acid (9-HN) is derived as a separate compound and later esterified tomonic acid to formpseudomonic acid.13C labeledacetate feeding has shown that C1-C6 are constructed with acetate in the canonical fashion offatty acid synthesis. C7' shows only C1 labeling of acetate, while C8' and C9' show a reversed pattern of 13C labeled acetate.[32] 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.[33]
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.[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.[27]
