Mupirocin

Source: Wikipedia, the free encyclopedia.
Not to be confused with
Miprocin
.

Mupirocin
Structural formula of pseudomonic acid A (PA-A), the principal component of mupirocin
Ball-and-stick model of the pseudomonic acid A molecule, the principal component of mupirocin
Pseudomonic acid A (PA-A), the principal component of mupirocin
Clinical data
Trade namesBactroban, others
Other namesmuciprocin[1]
AHFS/Drugs.comMonograph
MedlinePlusa688004
License data
Pregnancy
category
  • AU: B1
Topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding97%
Elimination half-life20 to 40 minutes
Identifiers
  • 9-[(E)-4-[(2S,3R,4R,5S)-3,4-dihydroxy-5-[[(2S,3S)-3-[(2S,3S)-3-hydroxybutan-2-yl]oxiran-2-yl]methyl]oxan-2-yl]-3-methylbut-2-enoyl]oxynonanoic acid
JSmol)
Melting point77 to 78 °C (171 to 172 °F)
  • O=C(O)CCCCCCCCOC(=O)\C=C(/C)C[C@@H]2OC[C@H](C[C@@H]1O[C@H]1[C@@H](C)[C@@H](O)C)[C@@H](O)[C@H]2O
  • InChI=1S/C26H44O9/c1-16(13-23(30)33-11-9-7-5-4-6-8-10-22(28)29)12-20-25(32)24(31)19(15-34-20)14-21-26(35-21)17(2)18(3)27/h13,17-21,24-27,31-32H,4-12,14-15H2,1-3H3,(H,28,29)/b16-13+/t17-,18-,19-,20-,21-,24+,25-,26-/m0/s1 checkY
  • Key:MINDHVHHQZYEEK-HBBNESRFSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Mupirocin, sold under the brand name Bactroban among others, is a topical

resistance, 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.

bacterial death.[6]

Mupirocin was initially isolated in 1971 from

generic medication.[13]

Medical uses

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.[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 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.[16]

Resistance

Shortly after the clinical use of mupirocin began, strains of Staphylococcus aureus that were

E. coli IleS, 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 as azelaic acid, nitrofurazone, silver sulfadiazine, and ramoplanin have been shown to be effective against MuH strains.[17]

Most strains of

acne vulgaris, are naturally resistant to mupirocin.[21]

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. [citation needed]

The mechanism of action of mupirocin differs from other clinical antibiotics, rendering cross-resistance to other antibiotics unlikely.[17] 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.[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 termed MupB. It was found in a Canadian MRSA isolate "MUP87" and is probably located on a nonconjugative plasmid.[22]

Mechanism of action

Pseudomonic acid inhibits

(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 with furanomycin, an analog 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]

Biosynthesis

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]
ketosynthase, TE=thioesterase
.

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,[29] pseudomonic acid C with a double bond between C10 and C11, instead of the epoxide 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]

Biosynthesis of pseudomonic acid A

The 74

enzymes and twenty-six other peptides (Table 1).[27] 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.[27] 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.[27] 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.[27]

Pseudomonic acid A is the product of an

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.[32]

Table 1: The biosynthetic gene cluster of mupirocin
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
transcriptional activator
mupX amidase/hydrolase
mupI N-AHL synthase

Monic acid biosynthesis

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-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.[citation needed]

Assembly of monic acid is continued by the transfer of the 12C product of MmpD to MmpA.[27]

Post-PKS tailoring

The keto group at C3 is replaced with a methyl group in a multi-step reaction (Figure 3). MupG begins by

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.[27]

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.[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]

The epoxide of PA-A at C10-11 is believed to be inserted after pyran formation by a cytochrome 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]

9-Hydroxy-nonanoic acid biosynthesis

The nine-carbon

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.[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 catalyzes 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]

References

  1. ISBN 9780071379953. Archived
    from the original on 10 September 2017.
  2. ^ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  3. ^ "Bactroban Product information". Health Canada. 22 October 2009. Archived from the original on 26 February 2023. Retrieved 26 February 2023.
  4. ^ "Bactroban (mupirocin) cream, for topical use Initial U.S. Approval: 1997". DailyMed. Archived from the original on 26 February 2023. Retrieved 26 February 2023.
  5. PMID 27184545
    .
  6. ^ a b c d e f g "Mupirocin". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  7. ^
    ISBN 9789241547659
    .
  8. ISBN 9780387789408. Archived
    from the original on 10 September 2017.
  9. ISBN 9780849351297. Archived
    from the original on 10 September 2017.
  10. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  11. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  12. ^ "Mupirocin - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  13. ^ "Competitive Generic Therapy Approvals". U.S. Food and Drug Administration (FDA). 29 June 2023. Archived from the original on 29 June 2023. Retrieved 29 June 2023.
  14. ^
    PMID 365175
    .
  15. ^ "Product Monograph Bactroban" (PDF). Archived (PDF) from the original on 24 September 2015. Retrieved 8 September 2014.
  16. PMID 30376041
    .
  17. ^
    PMID 9511032
    .
  18. ^ Worcester S (March 2008). "Topical MRSA Decolonization Is Warranted During Outbreaks". American College of Emergency Physicians. Elsevier Global Medical News. Archived from the original on 18 May 2014. Retrieved 18 November 2013.
  19. PMID 7929087
    .
  20. PMID 8431015
    .
  21. ^ "Antibiotic Susceptibility of Propionibacterium acnes". ScienceOfAcne.com. 11 June 2011. Archived from the original on 29 July 2012. Retrieved 27 August 2012.
  22. S2CID 21526116
    .
  23. PMID 4576025
    .
  24. PMID 4982424
    .
  25. PMID 11584022
    .
  26. S2CID 211263261
    .
  27. ^
    PMID 12770824
    .
  28. ^
    PMID 16039529
    .
  29. PMID 402373
    .
  30. doi:10.1016/S0040-4039(00)71533-4
    .
  31. doi:10.1039/P19830002655
    .
  32. ^
    PMID 402372
    .
  33. doi:10.1039/P19890000207
    .
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