Mupirocin, sold under the brand name Bactroban among others, is a topical antibiotic useful against superficial skin infections such as

impetigo Impetigo is a bacterial infection that involves the superficial skin. The most common presentation is yellowish crusts on the face, arms, or legs. Less commonly there may be large blisters which affect the groin or armpits. The lesions may be pa ...

folliculitis Folliculitis is the infection and inflammation of one or more hair follicles. The condition may occur anywhere on hair-covered skin. The rash may appear as pimples that come to white tips on the face, chest, back, arms, legs, buttocks, or head. ...

. It may also be used to get rid of methicillin-resistant ''S. aureus'' (MRSA) when present in the nose without symptoms. Due to concerns of developing resistance, use for greater than ten days is not recommended. It is used as a cream or ointment applied to the skin. Common side effects include itchiness and rash at the site of application, headache, and nausea. Long term use may result in increased growth of

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...

. Use during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

and

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...

appears to be safe. Mupirocin is in the carboxylic acid class of medications. It works by blocking a bacteria's ability to make protein, which usually results in bacterial death. Mupirocin was initially isolated in 1971 from '' Pseudomonas fluorescens''. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. In 2020, it was the 203rd most commonly prescribed medication in the United States, with more than 2million prescriptions.

Medical uses

Mupirocin is used as a topical treatment for bacterial skin infections (for example,

boil A boil, also called a furuncle, is a deep folliculitis, which is an infection of the hair follicle. It is most commonly caused by infection by the bacterium '' Staphylococcus aureus'', resulting in a painful swollen area on the skin caused by ...

, 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. Mupirocin is inactive for most anaerobic bacteria, mycobacteria, mycoplasma, chlamydia, yeast, and fungi. 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.

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. 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). Resistance in the MuL strains is probably due to

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

s in the organism's

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

isoleucyl-tRNA synthetase. In '' E. coli'' IleRS, a single amino acid mutation was shown to alter mupirocin resistance. MuH is linked to the acquisition of a separate Ile synthetase gene, MupA. Mupirocin is not a viable antibiotic against MuH strains. Other antibiotic agents, such as

azelaic acid Azelaic acid (AzA) is an organic compound with the formula HOOC(CH2)7 COOH. This saturated dicarboxylic acid exists as a white powder. It is found in wheat, rye, and barley. It is a precursor to diverse industrial products including polymers an ...

nitrofurazone Nitrofurazone (INN, trade name Furacin) is an antimicrobial organic compound belonging to the nitrofuran class. It is most commonly used as a topical antibiotic ointment. It is effective against gram-positive bacteria, gram-negative bacteria, ...

silver sulfadiazine Silver sulfadiazine, sold under the brand Silvadene among others, is a topical antibiotic used in partial thickness and full thickness burns to prevent infection. Tentative evidence has found other antibiotics to be more effective, and therefore ...

, and ramoplanin have been shown to be effective against MuH strains. Most strains of ''

Cutibacterium acnes ''Cutibacterium acnes'' (formerly ''Propionibacterium acnes'') is the relatively slow-growing, typically aerotolerant anaerobic, gram-positive bacterium (rod) linked to the skin condition of acne; it can also cause chronic blepharitis and endopht ...

'', a causative agent in the skin disease acne vulgaris, are naturally resistant to mupirocin. Most strains of ''Pseudomonas fluorescens'' are also resistant to mupirocin as they produce the antibiotic and it’s possible other species of ''

Pseudomonas ''Pseudomonas'' is a genus of Gram-negative, Gammaproteobacteria, belonging to the family Pseudomonadaceae and containing 191 described species. The members of the genus demonstrate a great deal of metabolic diversity and consequently are able t ...

'' may be resistant as well. The mechanism of action of mupirocin differs from other clinical antibiotics, rendering

cross-resistance Cross-resistance is when something develops resistance to several substances that have a similar mechanism of action. For example, if a certain type of bacteria develops resistance to one antibiotic, that bacteria will also have resistance to sev ...

to other antibiotics unlikely. However, the MupA gene may co-transfer with other antibacterial resistance genes. This has been observed already with resistance genes for

triclosan Triclosan (sometimes abbreviated as TCS) is an antibacterial and antifungal agent present in some consumer products, including toothpaste, soaps, detergents, toys, and surgical cleaning treatments. It is similar in its uses and mechanism of ac ...

tetracycline Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. Common side effects in ...

, and

trimethoprim Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia in peo ...

. It may also result in overgrowth of non-susceptible organisms.

Mechanism of action

Pseudomonic acid inhibits isoleucine tRNA synthetase in bacteria, 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. The combined inhibition of protein synthesis and RNA synthesis results in bacteriostasis. This mechanism of action is shared with furanomycin, an

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

of isoleucine.

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, pseudomonic acid C with a

double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betwee ...

between C10 and C11, instead of the

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

of PA-A, and pseudomonic acid D with a double bond at C4` and C5` in the 9-hydroxy-nonanoic acid portion of mupirocin.

Biosynthesis of pseudomonic acid A

The 74 kb mupirocin

gene cluster A gene family is a set of homologous genes within one organism. A gene cluster is a group of two or more genes found within an organism's DNA that encode similar polypeptides, or proteins, which collectively share a generalized function and are ...

contains six multi-domain enzymes and twenty-six other

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s (Table 1). Four large multi-domain type I

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

(PKS) proteins are encoded, as well as several single function enzymes with sequence similarity to type II PKSs. 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. The mupirocin pathway also contains several tandem

acyl carrier protein The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene ...

doublets or triplets. This may be an adaptation to increase the throughput rate or to bind multiple substrates simultaneously. Pseudomonic acid A is the product of an

esterification In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

between the 17C polyketide monic acid and the 9C

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

9-hydroxy-nonanoic acid. The possibility that the entire molecule is assembled as a single polyketide with a Baeyer-Villiger

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

inserting an

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...

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.

Monic acid biosynthesis

Biosynthesis of the 17C monic acid unit begins on MmpD (Figure 1). 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. Two more rounds of extension with malonyl-CoA units are achieved by module 5 and 6. Module 5 also contains a KR domain.

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 In the nomenclature of organic chemistry, a locant is a term to indicate the position of a functional group or substituent within a molecule. Numeric locants The International Union of Pure and Applied Chemistry (IUPAC) recommends the us ...

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. The formation of the

pyran In chemistry, pyran, or oxine, is a six-membered heterocyclic, non-aromatic ring, consisting of five carbon atoms and one oxygen atom and containing two double bonds. The molecular formula is C5H6O. There are two isomers of pyran that differ ...

ring requires many enzyme-mediated steps (Figure 4). The double bond between C8 and C9 is proposed to migrate to between C8 and C16. Gene knockout experiments of mupO, mupU, mupV, and macpE have eliminated PA-A production. 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. It is not known whether this occurs before or after the

of monic acid to 9-hydroxy-nonanoic acid. The

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

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

such as MupO. A gene knockout of mupO abolished PA-A production but PA-B, which also contains the C10-C11 epoxide, remained. This indicates that MupO is either not involved or is not essential for this epoxidation step.

9-Hydroxy-nonanoic acid biosynthesis

The nine-carbon

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 In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is co ...

. C7' shows only C1 labeling of acetate, while C8' and C9' show a reversed pattern of 13C labeled acetate. 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 -¹⁴Cor ,6-¹³C₂HMG. 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. 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. It also remains possible that 9-hydroxy-nonanoic acid is derived partially or entirely from outside of the mupirocin cluster.

References

External links

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