View source for Mupirocin

{{Short description|Chemical compound}}
{{Distinguish|Miprocin|}}
{{Use dmy dates|date=February 2024}}
{{Infobox drug
| Verifiedfields = changed
| verifiedrevid = 408766144
| image = Mupirocin structure.png
| image_class = skin-invert-image
| width = 320
| alt = Structural formula of pseudomonic acid A (PA-A), the principal component of mupirocin
| image2 = Mupirocin molecule ball.png
| alt2 = Ball-and-stick model of the pseudomonic acid A molecule, the principal component of mupirocin
| caption = Pseudomonic acid A (PA-A), the principal component of mupirocin

<!-- Clinical data -->
| pronounce = 
| tradename = Bactroban, others
| Drugs.com = {{drugs.com|monograph|mupirocin}}
| MedlinePlus = a688004
| DailyMedID = Mupirocin
| pregnancy_AU = B1
| pregnancy_AU_comment = 
| pregnancy_category =
| routes_of_administration = [[Topical administration|Topical]]
| class = 
| ATC_prefix = D06
| ATC_suffix = AX09
| ATC_supplemental = {{ATC|R01|AX06}}

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment = 
| legal_CA = OTC
| legal_CA_comment = <ref>{{cite web | title=Bactroban Product information | website=Health Canada | date=22 October 2009 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=15207 | access-date=26 February 2023 | archive-date=26 February 2023 | archive-url=https://web.archive.org/web/20230226053854/https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=15207 | url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = <ref name="Bactroban FDA label">{{cite web | title=Bactroban (mupirocin) cream, for topical use Initial U.S. Approval: 1997 | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=511949 | access-date=26 February 2023 | archive-date=26 February 2023 | archive-url=https://web.archive.org/web/20230226053857/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=511949 | url-status=live }}</ref>
| legal_EU = 
| legal_EU_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = 
| protein_bound = 97%
| metabolism = 
| metabolites = 
| onset = 
| elimination_half-life = 20 to 40 minutes
| duration_of_action = 
| excretion =

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 12650-69-0
| CAS_supplemental = 
| PubChem = 446596
| IUPHAR_ligand = 
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00410
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 393914
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = D0GX863OA5
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01076
| ChEBI_Ref = {{ebicite|changed|EBI}} 
| ChEBI = 7025
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 719
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = muciprocin<ref>{{cite book| vauthors = Fleischer AB |title=Emergency Dermatology: A Rapid Treatment Guide|date=2002|publisher=McGraw Hill Professional|isbn=9780071379953|page=173|url=https://books.google.com/books?id=YEk-H5mcgYcC|language=en|url-status=live|archive-url=https://web.archive.org/web/20170910183359/https://books.google.com/books?id=YEk-H5mcgYcC&q|archive-date=10 September 2017}}</ref>

<!-- Chemical and physical data -->
| IUPAC_name = 9-&#123;(''E'')-4-[(2''S'',3''R'',4''R'',5''S'')-3,4-dihydroxy-5-(&#123;(2''S'',3''S'')-3-[(2''S'',3''S'')-3-hydroxybutan-2-yl]oxiran-2-yl&#125;methyl)oxan-2-yl]-3-methylbut-2-enoyl&#125;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_Ref = {{stdinchicite|correct|chemspider}}
| 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_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MINDHVHHQZYEEK-HBBNESRFSA-N
| density = 
| density_notes = 
| melting_point = 77
| melting_high = 78
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

<!-- Definition and medical uses -->
'''Mupirocin''', sold under the brand name '''Bactroban''' among others, is a topical [[antibiotic]] useful against superficial [[skin infections]] such as [[impetigo]] or [[folliculitis]].<ref>{{cite journal | vauthors = AlHoufie ST, Foster HA | title = Effects of sub-lethal concentrations of mupirocin on global transcription in Staphylococcus aureus 8325-4 and a model for the escape from inhibition | journal = Journal of Medical Microbiology | volume = 65 | issue = 8 | pages = 858–866 | date = August 2016 | pmid = 27184545 | doi = 10.1099/jmm.0.000270 | doi-access = free }}</ref><ref name=AHFS2016>{{cite web|title=Mupirocin|url=https://www.drugs.com/monograph/mupirocin.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221005721/https://www.drugs.com/monograph/mupirocin.html|archive-date=21 December 2016}}</ref><ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | page = 298 }}</ref> It may also be used to get rid of [[methicillin-resistant S. aureus|methicillin-resistant ''S. aureus'']] (MRSA) when present in the nose without symptoms.<ref name=AHFS2016/> Due to concerns of developing [[antibiotic resistance|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/>

<!-- Side effects and mechanisms -->
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>{{cite book| vauthors = Khanna R, Krediet RT |title=Nolph and Gokal's Textbook of Peritoneal Dialysis|date=2009|publisher=Springer Science & Business Media |isbn=9780387789408|page=421|edition=3rd |url=https://books.google.com/books?id=hSkN5rbg6o0C&pg=PA421|language=en|url-status=live|archive-url=https://web.archive.org/web/20170910183359/https://books.google.com/books?id=hSkN5rbg6o0C&pg=PA421|archive-date=10 September 2017}}</ref> It works by blocking a bacteria's ability to make protein, which usually results in [[bactericidal|bacterial death]].<ref name=AHFS2016/>

<!-- History, society and culture -->
Mupirocin was initially isolated in 1971 from ''[[Pseudomonas fluorescens]]''.<ref>{{cite book| vauthors = Heggers JP, Robson MC, Phillips LG |title=Quantitative Bacteriology: Its Role in the Armamentarium of the Surgeon|date=1990|publisher=CRC Press|isbn=9780849351297|page=118|url=https://books.google.com/books?id=kfL2NCLE7SsC&pg=PA118|language=en|url-status=live|archive-url=https://web.archive.org/web/20170910183359/https://books.google.com/books?id=kfL2NCLE7SsC&pg=PA118|archive-date=10 September 2017}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In 2023, it was the 171st most commonly prescribed medication in the United States, with more than 2{{nbsp}}million prescriptions.<ref name="Top 300">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Mupirocin Drug Usage Statistics, United States, 2013 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Mupirocin | access-date = 19 August 2025 }}</ref> It is available as a [[generic medication]].<ref>{{cite web | title=Competitive Generic Therapy Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 June 2023 | url=https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | access-date=29 June 2023 | archive-date=29 June 2023 | archive-url=https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | url-status=dead }}</ref>

==Medical uses==
[[File:Tube Of Bactroban.jpg|thumb|A tube of Bactroban]]
Mupirocin is used as a topical treatment for bacterial skin infections (for example, [[boil]]s, [[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|methicillin-resistant ''Staphylococcus aureus'']] (MRSA) infections.<ref name="pmid365175">{{cite journal | vauthors = Hughes J, Mellows G | title = Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid | journal = The Biochemical Journal | volume = 176 | issue = 1 | pages = 305–318 | date = October 1978 | pmid = 365175 | pmc = 1186229 | doi = 10.1042/bj1760305 }}</ref> Mupirocin is inactive for most anaerobic bacteria, mycobacteria, mycoplasma, chlamydia, yeast, and fungi.<ref>{{cite web |url=http://www.skintherapyletter.com/download/BactOintPM.pdf |title=Product Monograph Bactroban |access-date=8 September 2014 |url-status=live |archive-url=https://web.archive.org/web/20150924102400/http://www.skintherapyletter.com/download/BactOintPM.pdf |archive-date=24 September 2015 }}</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>{{cite journal | vauthors = Troeman DP, Van Hout D, Kluytmans JA | title = Antimicrobial approaches in the prevention of Staphylococcus aureus infections: a review | journal = The Journal of Antimicrobial Chemotherapy | volume = 74 | issue = 2 | pages = 281–294 | date = February 2019 | pmid = 30376041 | pmc = 6337897 | doi = 10.1093/jac/dky421 }}</ref>

===Resistance===
Shortly after the clinical use of mupirocin began, strains of ''Staphylococcus aureus'' that were [[drug resistance|resistant]] to mupirocin emerged, with [[nares]] clearance rates of less than 30% success.<ref name="pmid9511032">{{cite journal | vauthors = Cookson BD | title = The emergence of mupirocin resistance: a challenge to infection control and antibiotic prescribing practice | journal = The Journal of Antimicrobial Chemotherapy | volume = 41 | issue = 1 | pages = 11–18 | date = January 1998 | pmid = 9511032 | doi = 10.1093/jac/41.1.11 | doi-access =  }}</ref><ref>{{cite web |url=http://www.acep.org/Clinical---Practice-Management/Topical-MRSA-Decolonization-Is-Warranted-During-Outbreaks/ |title=Topical MRSA Decolonization Is Warranted During Outbreaks | vauthors = Worcester S |date=March 2008 |website=American College of Emergency Physicians |publisher=Elsevier Global Medical News |access-date=18 November 2013 |url-status=live |archive-url=https://web.archive.org/web/20140518102556/http://www.acep.org/Clinical---Practice-Management/Topical-MRSA-Decolonization-Is-Warranted-During-Outbreaks/ |archive-date=18 May 2014 }}</ref> Two distinct populations of mupirocin-resistant ''S. aureus'' were isolated. One strain possessed low-level resistance (MuL: [[minimum inhibitory concentration|MIC]] = 8–256&nbsp;mg/L), and another possessed high-level resistance (MuH: MIC &gt; 256&nbsp;mg/L).<ref name="pmid9511032"/> Resistance in the MuL strains is probably due to [[mutation]]s in the organism's [[Wild type|wild-type]] [[isoleucyl-tRNA synthetase]] (''IleS''). In ''[[E. coli]]'' ''IleS'', a single amino acid mutation was shown to alter mupirocin resistance.<ref name="pmid7929087">{{cite journal | vauthors = Yanagisawa T, Lee JT, Wu HC, Kawakami M | title = 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 | journal = The Journal of Biological Chemistry | volume = 269 | issue = 39 | pages = 24304–24309 | date = September 1994 | pmid = 7929087 | doi = 10.1016/S0021-9258(19)51082-1 | doi-access = free }}</ref> MuH is linked to the acquisition of a separate Ile synthetase gene, ''MupA''.<ref name="pmid8431015">{{cite journal | vauthors = Gilbart J, Perry CR, Slocombe B | title = High-level mupirocin resistance in Staphylococcus aureus: evidence for two distinct isoleucyl-tRNA synthetases | journal = Antimicrobial Agents and Chemotherapy | volume = 37 | issue = 1 | pages = 32–38 | date = January 1993 | pmid = 8431015 | pmc = 187600 | doi = 10.1128/aac.37.1.32 }}</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>{{cite web |url=http://scienceofacne.com/antibiotic-susceptibility-of-propionibacterium-acnes/ |title=Antibiotic Susceptibility of Propionibacterium acnes. |publisher=ScienceOfAcne.com |date=11 June 2011 |access-date=27 August 2012 |url-status=live |archive-url=https://web.archive.org/web/20120729063418/http://scienceofacne.com/antibiotic-susceptibility-of-propionibacterium-acnes/ |archive-date=29 July 2012 }}</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.{{citation needed|date=February 2023}}

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 [[Cotransformation|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.{{citation needed|date=February 2023}}

A second type of high-level resistant synthetase was discovered in 2012 and termed ''MupB''. It was found in a Canadian [[Methicillin-resistant Staphylococcus aureus|MRSA]] isolate "MUP87" and is probably located on a nonconjugative plasmid.<ref>{{cite journal | vauthors = Seah C, Alexander DC, Louie L, Simor A, Low DE, Longtin J, Melano RG | title = MupB, a new high-level mupirocin resistance mechanism in Staphylococcus aureus | journal = Antimicrobial Agents and Chemotherapy | volume = 56 | issue = 4 | pages = 1916–1920 | date = April 2012 | pmid = 22252810 | doi = 10.1128/AAC.05325-11 | pmc = 3318397 | s2cid = 21526116 }}</ref>

==Mechanism of action==
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 [[Protein synthesis inhibitor|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">{{cite journal | vauthors = Haseltine WA, Block R | title = Synthesis of guanosine tetra- and pentaphosphate requires the presence of a codon-specific, uncharged transfer ribonucleic acid in the acceptor site of ribosomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 70 | issue = 5 | pages = 1564–1568 | date = May 1973 | pmid = 4576025 | pmc = 433543 | doi = 10.1073/pnas.70.5.1564 | doi-access = free | bibcode = 1973PNAS...70.1564H }}</ref> The combined inhibition of protein synthesis and RNA synthesis results in bacteriostasis.  This mechanism of action is shared with [[furanomycin]], an [[Functional analog (chemistry)|analog]] of isoleucine.<ref name="pmid4982424">{{cite journal | vauthors = Tanaka K, Tamaki M, Watanabe S | title = Effect of furanomycin on the synthesis of isoleucyl-tRNA | journal = Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis | volume = 195 | issue = 1 | pages = 244–245 | date = November 1969 | pmid = 4982424 | doi = 10.1016/0005-2787(69)90621-2 }}</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>{{cite journal | vauthors = Nakama T, Nureki O, Yokoyama S | title = Structural basis for the recognition of isoleucyl-adenylate and an antibiotic, mupirocin, by isoleucyl-tRNA synthetase | journal = The Journal of Biological Chemistry | volume = 276 | issue = 50 | pages = 47387–47393 | date = December 2001 | pmid = 11584022 | doi = 10.1074/jbc.M109089200 | doi-access = free }}</ref> Mupirocin is able to bind to bacterial and archaeal versions of the enzyme, but not eukaryotic versions.<ref>{{cite journal | vauthors = Chung S, Kim S, Ryu SH, Hwang KY, Cho Y | title = Structural Basis for the Antibiotic Resistance of Eukaryotic Isoleucyl-tRNA Synthetase | journal = Molecules and Cells | volume = 43 | issue = 4 | pages = 350–359 | date = April 2020 | pmid = 32088946 | doi = 10.14348/molcells.2020.2287 | pmc = 7191050 | s2cid = 211263261 }}</ref>

==Biosynthesis==
[[File:Monic acid4.png|class=skin-invert-image|thumb|upright=2|'''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=[[Acyltransferase|acyl transferase]], DH=[[dehydratase]], ER=enoyl reductase, HMG=[[3-hydroxy-3-methylglutaric acid]], MeT=[[Methyltransferase|methyl transferase]], KR=ketoreductase, KS=[[ketosynthase]], TE=[[thioesterase]].]]

[[File:Pseudomonic acid A-D.png|class=skin-invert-image|upright=2|thumb|'''Figure 2'''. The structure of pseudomonic acid A–D, labeled A to D, respectively]]

[[File:Mupirocin C15 methylation.png|class=skin-invert-image|thumb|upright=2|'''Figure 3'''. The C15 [[methyl group]] of monic acid is attached to C3 by the following reaction scheme. MupH is a [[Hydroxymethylglutaryl-CoA synthase|Hydroxymethylglutaryl-Coenzyme A synthase]], MupJ and MupK are [[Enoyl-CoA hydratase]]s.<ref name="pmid12770824"/>]]

[[File:Mupirocin pyran2.png|class=skin-invert-image|thumb|upright=2|'''Figure 4'''. The [[pyran]] ring of mupirocin is generated in this proposed multistep reaction. [[Gene knockout]]s of mupO, mupU, mupV and macpE abolish PA-A production but not PA-B production, demonstrating that PA-B is a [[Precursor (chemistry)|precursor]] to PA-A.<ref name="pmid16039529"/>]]

[[File:9-HNA.png|class=skin-invert-image|thumb|upright=2|'''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 [[Hydroxy group|hydroxyl group]] at C8,<ref name="pmid402373">{{cite journal | vauthors = Chain EB, Mellows G | title = Pseudomonic acid. Part 3. Structure of pseudomonic acid B | journal = Journal of the Chemical Society, Perkin Transactions 1 | issue = 3 | pages = 318–324 | year = 1977 | pmid = 402373 | doi = 10.1039/p19770000318 }}</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">{{cite journal | vauthors = Clayton JP, O'Hanlon PJ, Rogers NH |doi=10.1016/S0040-4039(00)71533-4 |title= The structure and configuration of pseudomonic acid C |year=1980 |journal=Tetrahedron Letters |volume=21 |pages=881–884 |issue=9 }}</ref> and pseudomonic acid D with a double bond at C4` and C5` in the 9-hydroxy-nonanoic acid portion of mupirocin.<ref>{{cite journal| vauthors = O'Hanlon PJ, Rogers NH, Tyler JW | title = The chemistry of pseudomonic acid. Part 6. Structure and preparation of pseudomonic acid D| doi = 10.1039/P19830002655| journal = Journal of the Chemical Society, Perkin Transactions 1| pages = 2655–2657| year = 1983}}</ref>

===Biosynthesis of pseudomonic acid A===
The 74 [[Kilobase|kb]] mupirocin [[gene cluster]] contains six [[protein domain|multi-domain]] [[enzymes]] and twenty-six other [[peptide]]s (Table 1).<ref name="pmid12770824">{{cite journal | vauthors = El-Sayed AK, Hothersall J, Cooper SM, Stephens E, Simpson TJ, Thomas CM | title = Characterization of the mupirocin biosynthesis gene cluster from Pseudomonas fluorescens NCIMB 10586 | journal = Chemistry & Biology | volume = 10 | issue = 5 | pages = 419–430 | date = May 2003 | pmid = 12770824 | doi = 10.1016/S1074-5521(03)00091-7 | doi-access = free }}</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">{{cite journal | vauthors = Feline TC, Jones RB, Mellows G, Phillips L | title = Pseudomonic acid. Part 2. Biosynthesis of pseudomonic acid A | journal = Journal of the Chemical Society, Perkin Transactions 1 | issue = 3 | pages = 309–318 | year = 1977 | pmid = 402372 | doi = 10.1039/p19770000309 }}</ref>

{| class="wikitable"
|+Table 1: The biosynthetic gene cluster of mupirocin
|-
! Gene
! Function
|-
| mupA
| [[Flavin mononucleotide|FMN]]H<sub>2</sub> dependent oxygenase
|-
| mmpA
| [[ketosynthase|KS]] [[acyl carrier protein|ACP]] KS [[ketoreductase|KR]] ACP KS ACP ACP
|-
| mupB
| 3-oxoacyl-ACP synthase
|-
| mmpB
| KS [[dehydratase|DH]] KR ACP ACP ACP [[thioesterase|TE]]
|-
| mmpC
| [[acyltransferase|AT]] AT
|-
| mmpD
| KS DH KR [[methyltransferase|MeT]] ACP KS DH KR ACP KS DH KR MeT ACP KS KR ACP
|-
| mupC
| [[Nicotinamide adenine dinucleotide|NADH]]/[[Nicotinamide adenine dinucleotide phosphate|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
| [[Hydroxymethylglutaryl-CoA synthase|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-acyl homoserine lactone|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).<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 sequence|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|date=February 2023}}

Assembly of monic acid is continued by the transfer of the 12C product of MmpD to MmpA.<ref name="pmid12770824"/>

===Post-PKS tailoring===

The keto group at C3 is replaced with a methyl group in a multi-step reaction (Figure 3). MupG begins by [[Decarboxylation|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">{{cite journal | vauthors = Cooper SM, Laosripaiboon W, Rahman AS, Hothersall J, El-Sayed AK, Winfield C, Crosby J, Cox RJ, Simpson TJ, Thomas CM | display-authors = 6 | title = Shift to Pseudomonic acid B production in P. fluorescens NCIMB10586 by mutation of mupirocin tailoring genes mupO, mupU, mupV, and macpE | journal = Chemistry & Biology | volume = 12 | issue = 7 | pages = 825–833 | date = July 2005 | pmid = 16039529 | doi = 10.1016/j.chembiol.2005.05.015 | name-list-style = vanc | doi-access = free }}</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 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]]. <sup>13</sup>C 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-<sup>14</sup>C] or [3,6-<sup>13</sup>C<sub>2</sub>]-HMG.<ref>{{cite journal| vauthors = Martin FM, Simpson TJ | doi = 10.1039/P19890000207| title = Biosynthetic studies on pseudomonic acid (mupirocin), a novel antibiotic metabolite of Pseudomonas fluorescens| journal = Journal of the Chemical Society, Perkin Transactions 1| pages = 207–209| year = 1989 | issue=1}}</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"/>
{{clear}}

== References ==
{{Reflist}}

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[[Category:Antibiotics]]
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[[Category:Epoxides]]
[[Category:Fatty acids]]
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[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]