Chemistry:Mupirocin

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Short description: Chemical compound
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
Routes of
administration		Topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding97%
Elimination half-life20 to 40 minutes
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC26H44O9
Molar mass500.629 g·mol−1
3D model (JSmol)
Melting point77 to 78 °C (171 to 172 °F)
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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.[4][5][6] It may also be used to get rid of methicillin-resistant S. aureus (MRSA) when present in the nose without symptoms.[5] Due to concerns of developing resistance, use for greater than ten days is not recommended.[6] It is used as a cream or ointment applied to the skin.[5]

Common side effects include itchiness and rash at the site of application, headache, and nausea.[5] Long term use may result in increased growth of fungi.[5] Use during pregnancy and breastfeeding appears to be safe.[5] Mupirocin is chemically a carboxylic acid.[7] It works by blocking a bacteria's ability to make protein, which usually results in bacterial death.[5]

Mupirocin was initially isolated in 1971 from Pseudomonas fluorescens.[8] It is on the World Health Organization's List of Essential Medicines.[9] In 2020, it was the 203rd most commonly prescribed medication in the United States, with more than 2 million prescriptions.[10][11] It is available as a generic medication.[12]

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.[13] Mupirocin is inactive for most anaerobic bacteria, mycobacteria, mycoplasma, chlamydia, yeast, and fungi.[14]

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.[15]

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.[16][17] 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).[16] 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.[18] MuH is linked to the acquisition of a separate Ile synthetase gene, MupA.[19] 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.[16]

Most strains of Cutibacterium acnes, a causative agent in the skin disease acne vulgaris, are naturally resistant to mupirocin.[20]

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.[16] 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.[16] 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.[21]

Mechanism of action

Pseudomonic acid inhibits isoleucine—tRNA ligase in bacteria,[13] 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.[22] The combined inhibition of protein synthesis and RNA synthesis results in bacteriostasis. This mechanism of action is shared with furanomycin, an analog of isoleucine.[23]

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.[24] Mupirocin is able to bind to bacterial and archaeal versions of the enzyme, but not eukaryotic versions.[25]

Biosynthesis

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.
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.[26]
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.[27]
Figure 5. MmpB is proposed to synthesize 9-HN with a 3-hydroxy-propionate starter unit and three malonyl-CoA extender units. The domain structure of MmpB is shown below alongside MupE, the proposed enoyl reductase required for complete saturation of 9-HN. ACP=acyl carrier protein, DH=dehydratase, ER=enoyl reductase, KR=ketoreductase, KS=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,[28] pseudomonic acid C with a double bond between C10 and C11, instead of the epoxide of PA-A,[29] and pseudomonic acid D with a double bond at C4` and C5` in the 9-hydroxy-nonanoic acid portion of mupirocin.[30]

Biosynthesis of pseudomonic acid A

The 74 kb mupirocin gene cluster contains six multi-domain enzymes and twenty-six other peptides (Table 1).[26] 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.[26] 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.[26] 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.[26]

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
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 biosynthesis

Biosynthesis of the 17C monic acid unit begins on MmpD (Figure 1).[26] 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.[26]

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.[26]

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.[27] Gene knockout experiments of mupO, mupU, mupV, and macpE have eliminated PA-A production.[27] 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.[27]

The epoxide of PA-A at C10-11 is believed to be inserted after pyran formation by a cytochrome P450 such as MupO.[26] A gene knockout of mupO abolished PA-A production but PA-B, which also contains the C10-C11 epoxide, remained.[27]

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 [3-14C] or [3,6-13C2]-HMG.[32]

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.[26] 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.[26]

References

  1. ↑ (in en) Emergency Dermatology: A Rapid Treatment Guide. McGraw Hill Professional. 2002. p. 173. ISBN 9780071379953. https://books.google.com/books?id=YEk-H5mcgYcC. 
  2. ↑ "Bactroban Product information". 22 October 2009. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=15207. 
  3. ↑ "Bactroban (mupirocin) cream, for topical use Initial U.S. Approval: 1997". https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=511949. 
  4. ↑ "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. doi:10.1099/jmm.0.000270. PMID 27184545. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Mupirocin". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/mupirocin.html. 
  6. ↑ 6.0 6.1 WHO Model Formulary 2008. World Health Organization. 2009. p. 298. ISBN 9789241547659. 
  7. ↑ (in en) Nolph and Gokal's Textbook of Peritoneal Dialysis (3rd ed.). Springer Science & Business Media. 2009. p. 421. ISBN 9780387789408. https://books.google.com/books?id=hSkN5rbg6o0C&pg=PA421. 
  8. ↑ (in en) Quantitative Bacteriology: Its Role in the Armamentarium of the Surgeon. CRC Press. 1990. p. 118. ISBN 9780849351297. https://books.google.com/books?id=kfL2NCLE7SsC&pg=PA118. 
  9. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  11. ↑ "Mupirocin - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Mupirocin. 
  12. ↑ "Competitive Generic Therapy Approvals". 29 June 2023. https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals. 
  13. ↑ 13.0 13.1 "Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid". The Biochemical Journal 176 (1): 305–318. October 1978. doi:10.1042/bj1760305. PMID 365175. 
  14. ↑ "Product Monograph Bactroban". http://www.skintherapyletter.com/download/BactOintPM.pdf. 
  15. ↑ "Antimicrobial approaches in the prevention of Staphylococcus aureus infections: a review". The Journal of Antimicrobial Chemotherapy 74 (2): 281–294. February 2019. doi:10.1093/jac/dky421. PMID 30376041. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 "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. doi:10.1093/jac/41.1.11. PMID 9511032. 
  17. ↑ "Topical MRSA Decolonization Is Warranted During Outbreaks". Elsevier Global Medical News. March 2008. http://www.acep.org/Clinical---Practice-Management/Topical-MRSA-Decolonization-Is-Warranted-During-Outbreaks/. 
  18. ↑ "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. doi:10.1016/S0021-9258(19)51082-1. PMID 7929087. 
  19. ↑ "High-level mupirocin resistance in Staphylococcus aureus: evidence for two distinct isoleucyl-tRNA synthetases". Antimicrobial Agents and Chemotherapy 37 (1): 32–38. January 1993. doi:10.1128/aac.37.1.32. PMID 8431015. 
  20. ↑ "Antibiotic Susceptibility of Propionibacterium acnes.". ScienceOfAcne.com. 2011-06-11. http://scienceofacne.com/antibiotic-susceptibility-of-propionibacterium-acnes/. 
  21. ↑ "MupB, a new high-level mupirocin resistance mechanism in Staphylococcus aureus". Antimicrobial Agents and Chemotherapy 56 (4): 1916–1920. April 2012. doi:10.1128/AAC.05325-11. PMID 22252810. 
  22. ↑ "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. doi:10.1073/pnas.70.5.1564. PMID 4576025. Bibcode: 1973PNAS...70.1564H. 
  23. ↑ "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. doi:10.1016/0005-2787(69)90621-2. PMID 4982424. 
  24. ↑ "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. doi:10.1074/jbc.M109089200. PMID 11584022. 
  25. ↑ "Structural Basis for the Antibiotic Resistance of Eukaryotic Isoleucyl-tRNA Synthetase". Molecules and Cells 43 (4): 350–359. April 2020. doi:10.14348/molcells.2020.2287. PMID 32088946. 
  26. ↑ 26.00 26.01 26.02 26.03 26.04 26.05 26.06 26.07 26.08 26.09 26.10 "Characterization of the mupirocin biosynthesis gene cluster from Pseudomonas fluorescens NCIMB 10586". Chemistry & Biology 10 (5): 419–430. May 2003. doi:10.1016/S1074-5521(03)00091-7. PMID 12770824. 
  27. ↑ 27.0 27.1 27.2 27.3 27.4 "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. doi:10.1016/j.chembiol.2005.05.015. PMID 16039529. 
  28. ↑ "Pseudomonic acid. Part 3. Structure of pseudomonic acid B". Journal of the Chemical Society, Perkin Transactions 1 (3): 318–324. 1977. doi:10.1039/p19770000318. PMID 402373. 
  29. ↑ "The structure and configuration of pseudomonic acid C". Tetrahedron Letters 21 (9): 881–884. 1980. doi:10.1016/S0040-4039(00)71533-4. 
  30. ↑ "The chemistry of pseudomonic acid. Part 6. Structure and preparation of pseudomonic acid D". Journal of the Chemical Society, Perkin Transactions 1: 2655–2657. 1983. doi:10.1039/P19830002655. 
  31. ↑ 31.0 31.1 "Pseudomonic acid. Part 2. Biosynthesis of pseudomonic acid A". Journal of the Chemical Society, Perkin Transactions 1 (3): 309–318. 1977. doi:10.1039/p19770000309. PMID 402372. 
  32. ↑ "Biosynthetic studies on pseudomonic acid (mupirocin), a novel antibiotic metabolite of Pseudomonas fluorescens". Journal of the Chemical Society, Perkin Transactions 1 (1): 207–209. 1989. doi:10.1039/P19890000207. 

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