Mupirocin Explained

Verifiedfields:changed
Verifiedrevid:408766144
Width:320
Alt2:Ball-and-stick model of the pseudomonic acid A molecule, the principal component of mupirocin
Tradename:Bactroban, others
Dailymedid:Mupirocin
Pregnancy Au:B1
Routes Of Administration:Topical
Atc Prefix:D06
Atc Suffix:AX09
Legal Au:S4
Legal Au Comment:[1]
Legal Ca:OTC
Legal Ca Comment:[2]
Legal Uk:POM
Legal Us:Rx-only
Legal Us Comment:[3]
Protein Bound:97%
Elimination Half-Life:20 to 40 minutes
Cas Number:12650-69-0
Pubchem:446596
Drugbank:DB00410
Chemspiderid:393914
Unii:D0GX863OA5
Kegg:D01076
Chebi:7025
Chembl:719
Synonyms:muciprocin[4]
Iupac Name: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
C:26
H:44
O:9
Smiles: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
Stdinchi: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
Stdinchikey:MINDHVHHQZYEEK-HBBNESRFSA-N
Melting Point:77
Melting High:78

Mupirocin, sold under the brand name Bactroban among others, is a topical antibiotic useful against superficial skin infections such as impetigo or folliculitis.[5] [6] [7] It may also be used to get rid of methicillin-resistant S. aureus (MRSA) when present in the nose without symptoms.[6] Due to concerns of developing 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.[6] Long term use may result in increased growth of fungi.[6] Use during pregnancy and breastfeeding appears to be safe.[6] Mupirocin is chemically a carboxylic acid.[8] It works by blocking a bacteria's ability to make protein, which usually results in bacterial death.[6]

Mupirocin was initially isolated in 1971 from Pseudomonas fluorescens.[9] It is on the World Health Organization's List of Essential Medicines.[10] In 2021, it was the 203rd most commonly prescribed medication in the United States, with more than 2million prescriptions.[11] [12] It is available as a generic medication.[13]

Medical uses

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 resistant to mupirocin emerged, with nares clearance rates of less than 30% success.[17] [18] 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).[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.[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 Cutibacterium acnes, a causative agent in the skin disease 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.

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.

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 isoleucine—tRNA ligase in bacteria,[14] 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.[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

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,[27] pseudomonic acid C with a double bond between C10 and C11, instead of the epoxide of PA-A,[28] and pseudomonic acid D with a double bond at C4` and C5` in the 9-hydroxy-nonanoic acid portion of mupirocin.[29]

Biosynthesis of pseudomonic acid A

The 74 kb mupirocin gene cluster contains six multi-domain enzymes and twenty-six other peptides (Table 1).[30] 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.[30] 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.[30] 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.[30]

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.[31]

Table 1: The biosynthetic gene cluster of mupirocin
GeneFunction
mupAFMNH2 dependent oxygenase
mmpAKS ACP KS KR ACP KS ACP ACP
mupB3-oxoacyl-ACP synthase
mmpBKS DH KR ACP ACP ACP TE
mmpCAT AT
mmpDKS DH KR MeT ACP KS DH KR ACP KS DH KR MeT ACP KS KR ACP
mupCNADH/NADPH oxidoreductase
macpAACP
mupD3-oxoacyl-ACP reductase
mupEenoyl reductase
macpBACP
mupFKR
macpCACP
mupG3-oxoacyl-ACP synthase I
mupHHMG-CoA synthase
mupJenoyl-CoA hydratase
mupKenoyl-CoA hydratase
mmpEKS hydrolase
mupLputative hydrolase
mupMisoleucyl-tRNA synthase
mupNphosphopantetheinyl transferase
mupOcytochrome P450
mupPunknown
mupQacyl-CoA synthase
mupS3-oxoacyl-ACP reductase
macpDACP
mmpFKS
macpEACP
mupTferredoxin dioxygenase
mupUacyl-CoA synthase
mupVoxidoreductase
mupWdioxygenase
mupRN-AHL-responsive transcriptional activator
mupXamidase/hydrolase
mupIN-AHL synthase

Monic acid biosynthesis

Biosynthesis of the 17C monic acid unit begins on MmpD (Figure 1).[30] 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.

Assembly of monic acid is continued by the transfer of the 12C product of MmpD to MmpA.[30]

Post-PKS tailoring

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.[30]

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.[32] Gene knockout experiments of mupO, mupU, mupV, and macpE have eliminated PA-A production.[32] 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.[32]

The epoxide of PA-A at C10-11 is believed to be inserted after pyran formation by a cytochrome P450 such as MupO.[30] A gene knockout of mupO abolished PA-A production but PA-B, which also contains the C10-C11 epoxide, remained.[32]

9-Hydroxy-nonanoic acid biosynthesis

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.[31] 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-<sup>14</sup>C] or [3,6-<sup>13</sup>C<sub>2</sub>]-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.[30] 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.[30]

Notes and References

  1. Web site: Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 30 March 2024.
  2. Web site: Bactroban Product information . Health Canada . 22 October 2009 . 26 February 2023 . 26 February 2023 . https://web.archive.org/web/20230226053854/https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=15207 . live .
  3. Web site: Bactroban (mupirocin) cream, for topical use Initial U.S. Approval: 1997 . DailyMed . 26 February 2023 . 26 February 2023 . https://web.archive.org/web/20230226053857/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=511949 . live .
  4. Book: Fleischer AB . Emergency Dermatology: A Rapid Treatment Guide. 2002. McGraw Hill Professional. 9780071379953. 173. en. live. https://web.archive.org/web/20170910183359/https://books.google.com/books?id=YEk-H5mcgYcC&q. 10 September 2017.
  5. AlHoufie ST, Foster HA . Effects of sub-lethal concentrations of mupirocin on global transcription in Staphylococcus aureus 8325-4 and a model for the escape from inhibition . Journal of Medical Microbiology . 65 . 8 . 858–866 . August 2016 . 27184545 . 10.1099/jmm.0.000270 . free .
  6. Web site: Mupirocin. The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20161221005721/https://www.drugs.com/monograph/mupirocin.html. 21 December 2016.
  7. Book: WHO Model Formulary 2008 . 2009 . 9789241547659 . ((World Health Organization)) . Stuart MC, Kouimtzi M, Hill SR . 10665/44053 . World Health Organization . World Health Organization . 298 .
  8. Book: Khanna R, Krediet RT . Nolph and Gokal's Textbook of Peritoneal Dialysis. 2009. Springer Science & Business Media . 9780387789408. 421. 3rd . en. live. https://web.archive.org/web/20170910183359/https://books.google.com/books?id=hSkN5rbg6o0C&pg=PA421. 10 September 2017.
  9. Book: Heggers JP, Robson MC, Phillips LG . Quantitative Bacteriology: Its Role in the Armamentarium of the Surgeon. 1990. CRC Press. 9780849351297. 118. en. live. https://web.archive.org/web/20170910183359/https://books.google.com/books?id=kfL2NCLE7SsC&pg=PA118. 10 September 2017.
  10. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  11. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  12. Web site: Mupirocin - Drug Usage Statistics . ClinCalc . 14 January 2024.
  13. Web site: Competitive Generic Therapy Approvals . U.S. Food and Drug Administration (FDA) . 29 June 2023 . 29 June 2023 . 29 June 2023 . https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals . live .
  14. Hughes J, Mellows G . Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid . The Biochemical Journal . 176 . 1 . 305–318 . October 1978 . 365175 . 1186229 . 10.1042/bj1760305 .
  15. Web site: Product Monograph Bactroban . 8 September 2014 . live . https://web.archive.org/web/20150924102400/http://www.skintherapyletter.com/download/BactOintPM.pdf . 24 September 2015 .
  16. Troeman DP, Van Hout D, Kluytmans JA . Antimicrobial approaches in the prevention of Staphylococcus aureus infections: a review . The Journal of Antimicrobial Chemotherapy . 74 . 2 . 281–294 . February 2019 . 30376041 . 6337897 . 10.1093/jac/dky421 .
  17. Cookson BD . The emergence of mupirocin resistance: a challenge to infection control and antibiotic prescribing practice . The Journal of Antimicrobial Chemotherapy . 41 . 1 . 11–18 . January 1998 . 9511032 . 10.1093/jac/41.1.11 .
  18. Web site: Topical MRSA Decolonization Is Warranted During Outbreaks . Worcester S . March 2008 . American College of Emergency Physicians . Elsevier Global Medical News . 18 November 2013 . live . https://web.archive.org/web/20140518102556/http://www.acep.org/Clinical---Practice-Management/Topical-MRSA-Decolonization-Is-Warranted-During-Outbreaks/ . 18 May 2014 .
  19. Yanagisawa T, Lee JT, Wu HC, Kawakami M . Relationship of protein structure of isoleucyl-tRNA synthetase with pseudomonic acid resistance of Escherichia coli. A proposed mode of action of pseudomonic acid as an inhibitor of isoleucyl-tRNA synthetase . The Journal of Biological Chemistry . 269 . 39 . 24304–24309 . September 1994 . 7929087 . 10.1016/S0021-9258(19)51082-1 . free .
  20. Gilbart J, Perry CR, Slocombe B . High-level mupirocin resistance in Staphylococcus aureus: evidence for two distinct isoleucyl-tRNA synthetases . Antimicrobial Agents and Chemotherapy . 37 . 1 . 32–38 . January 1993 . 8431015 . 187600 . 10.1128/aac.37.1.32 .
  21. Web site: Antibiotic Susceptibility of Propionibacterium acnes. . ScienceOfAcne.com . 11 June 2011 . 27 August 2012 . live . https://web.archive.org/web/20120729063418/http://scienceofacne.com/antibiotic-susceptibility-of-propionibacterium-acnes/ . 29 July 2012 .
  22. Seah C, Alexander DC, Louie L, Simor A, Low DE, Longtin J, Melano RG . MupB, a new high-level mupirocin resistance mechanism in Staphylococcus aureus . Antimicrobial Agents and Chemotherapy . 56 . 4 . 1916–1920 . April 2012 . 22252810 . 10.1128/AAC.05325-11 . 3318397 . 21526116 .
  23. Haseltine WA, Block R . Synthesis of guanosine tetra- and pentaphosphate requires the presence of a codon-specific, uncharged transfer ribonucleic acid in the acceptor site of ribosomes . Proceedings of the National Academy of Sciences of the United States of America . 70 . 5 . 1564–1568 . May 1973 . 4576025 . 433543 . 10.1073/pnas.70.5.1564 . free . 1973PNAS...70.1564H .
  24. Tanaka K, Tamaki M, Watanabe S . Effect of furanomycin on the synthesis of isoleucyl-tRNA . Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis . 195 . 1 . 244–245 . November 1969 . 4982424 . 10.1016/0005-2787(69)90621-2 .
  25. Nakama T, Nureki O, Yokoyama S . Structural basis for the recognition of isoleucyl-adenylate and an antibiotic, mupirocin, by isoleucyl-tRNA synthetase . The Journal of Biological Chemistry . 276 . 50 . 47387–47393 . December 2001 . 11584022 . 10.1074/jbc.M109089200 . free .
  26. Chung S, Kim S, Ryu SH, Hwang KY, Cho Y . Structural Basis for the Antibiotic Resistance of Eukaryotic Isoleucyl-tRNA Synthetase . Molecules and Cells . 43 . 4 . 350–359 . April 2020 . 32088946 . 10.14348/molcells.2020.2287 . 7191050 . 211263261 .
  27. Chain EB, Mellows G . Pseudomonic acid. Part 3. Structure of pseudomonic acid B . Journal of the Chemical Society, Perkin Transactions 1 . 3 . 318–324 . 1977 . 402373 . 10.1039/p19770000318 .
  28. Clayton JP, O'Hanlon PJ, Rogers NH . 10.1016/S0040-4039(00)71533-4 . The structure and configuration of pseudomonic acid C . 1980 . Tetrahedron Letters . 21 . 881–884 . 9 .
  29. O'Hanlon PJ, Rogers NH, Tyler JW . The chemistry of pseudomonic acid. Part 6. Structure and preparation of pseudomonic acid D. 10.1039/P19830002655. Journal of the Chemical Society, Perkin Transactions 1. 2655–2657. 1983.
  30. El-Sayed AK, Hothersall J, Cooper SM, Stephens E, Simpson TJ, Thomas CM . Characterization of the mupirocin biosynthesis gene cluster from Pseudomonas fluorescens NCIMB 10586 . Chemistry & Biology . 10 . 5 . 419–430 . May 2003 . 12770824 . 10.1016/S1074-5521(03)00091-7 . free .
  31. Feline TC, Jones RB, Mellows G, Phillips L . Pseudomonic acid. Part 2. Biosynthesis of pseudomonic acid A . Journal of the Chemical Society, Perkin Transactions 1 . 3 . 309–318 . 1977 . 402372 . 10.1039/p19770000309 .
  32. Cooper SM, Laosripaiboon W, Rahman AS, Hothersall J, El-Sayed AK, Winfield C, Crosby J, Cox RJ, Simpson TJ, Thomas CM . 6 . Shift to Pseudomonic acid B production in P. fluorescens NCIMB10586 by mutation of mupirocin tailoring genes mupO, mupU, mupV, and macpE . Chemistry & Biology . 12 . 7 . 825–833 . July 2005 . 16039529 . 10.1016/j.chembiol.2005.05.015 . vanc . free .
  33. Martin FM, Simpson TJ . 10.1039/P19890000207. Biosynthetic studies on pseudomonic acid (mupirocin), a novel antibiotic metabolite of Pseudomonas fluorescens. Journal of the Chemical Society, Perkin Transactions 1. 207–209. 1989 . 1.