12650-69-0 Usage
Description
Mupirocin, also known as pseudomonic acid A or Bactroban, is a topical antibiotic produced by Pseudomonas fluorescens. It is a white crystalline solid with a melting point of 77-78°C and is characterized by its unique mode of action, specifically inhibiting bacterial protein synthesis by reversibly binding to isoleucine transfer RNA synthetase.
Uses
Used in Pharmaceutical Industry:
Mupirocin is used as a topical antibiotic for the treatment of dermal infections, particularly those involving Staphylococcus aureus and Staphylococcus epidermidis. It is effective against a range of Gram-positive and some Gram-negative bacteria, including cocci such as streptococci and Neisseria spp., but has limited activity against most Gram-negative and Gram-positive bacilli, except for Haemophilus influenzae.
Used in Topical Antibacterial Treatments:
Mupirocin is used as an antibiotic inhibitor of isoleucyl-tRNA synthetase, preventing the incorporation of isoleucine into bacterial proteins and stopping protein synthesis in susceptible bacteria. This makes it a potent and selective inhibitor for treating skin infections such as impetigo, eczema, and folliculitis that are secondarily infected by susceptible bacteria.
Used in Vasodilator Applications:
Although not explicitly mentioned in the provided materials, mupirocin's vasodilator properties could potentially be utilized in applications related to improving blood flow or managing conditions where vasodilation is beneficial.
Brand Names:
Mupirocin is available under various brand names, including Bactroban (GlaxoSmithKline) and Centany (Johnson & Johnson), indicating its widespread use and recognition in the pharmaceutical market.
Topical antibiotics
The crude drug of Bactroban ointment produced by the well-known domestic pharmaceutical company SmithKline is mupirocin which is a new type of local topical antibiotic and a kind of metabolic substance produced in the culture solution of pseudomonas fluorescence, that is, Pseudomonas A. Mainly through reversibly combined with isoleucine transfer RNA synthetase, this product can prevent the isoleucine incorporation and terminate the protein synthesis in cells containing isoleucine, leading to bacterial death. At low concentrations, this product has the inhibitory effect and at high concentrations, it has the bactericidal effect. This product is highly sensitive to a variety of gram-positive bacteria associated with skin infections, particularly staphylococcus aureus (including drug-resistant staphylococcus aureus) and streptococcus pyogenes; and it is also available for listeria monocytogenes and erythema erysipelothrix bacteria; it is generally not sensitive to gram-negative bacteria, but have some antibacterial effect on some Gram-negative bacteria such as E. coli, neisseria, haemophilus influenzae and Neisseria gonorrhoeae and is not sensitive to the majority of anaerobic bacteria and the normal flora of the skin and has low efficacy against fungi. Rate of occurrence is very low in vitro resistant mutants. After applied into the skin, this medicine can penetrate into the stratum corneum, but the absorption rate is very low. The binding rate of this drug and human serum protein is 95%. when absorbed, it is rapidly metabolized to an inactive substance single spore acid (Monic Acid) and excreted by the kidneys. The minimum inhibitory concentration of most sensitive staphylococcus is 0.01-0.25mg/L, that of sensitive streptococcus is 0.06-0.5mg/L, and that of listeriosis is 8mg/L. This product is more effective in vitro tests under acidic conditions than that under alkaline conditions. When human serum exists, activity of this drug reduce to 1/10-1/20.
Side effects
Topical application of this drug is generally no adverse reactions, occasionally with skin burning sensation, stinging sensation, aminotransferase rising, itching, dryness and erythema. Its occurrence rate is very low(3%) with a lesser degree. The medicine is generally tolerated and without being stopped. For long-term use, this drug may result in overgrowth of non-susceptible strains; nasal agent can cause headache, taste disturbance, rhinitis, pharyngitis, and other respiratory disorders.
The above information is edited by the Chemiclbook of Bai Linlin.
Side effects
Topical applications are well tolerated. Conjunctival application is contraindicated as it may cause irritation. Minor side effects such as irritation and unpleasant or abnormal taste have been recorded for very few patients following nasal application.Polyethylene glycol from the ointment base may, if absorbed from application to open wounds or damaged skin, cause renal toxicity.
Precautions
1. Allergies of pseudomonas acid or polyethylene glycol are disabled to use; patients who suffer from moderate or severe renal impairment use it with caution; the impact on pregnant or lactating women are not clear, temporarily not available.
2. Ointments made from polyethylene glycol which is used as a substrate, is only available for a small area of skin bacterial infection, and cannot be used to extensive burns or wounds so as to prevent the renal damage due to the absorption of polyethylene glycol, as well as mucous membranes, for example, used in the eyes and noses. As with nasal staph infections, the use of ointment base should be replaced by vaseline.
3. Although mupirocin toxicity is low, we should avoid the abuse or the use of the drug for a long term in case of generating drug-resistant strains.
Production Methods
It is a kind of substance produced by the pseudomonas fluorescence, including pseudomonic acids A, B, C, D. Mupirocin is pseudomonic acid A which is the major metabolite.
Originator
Beecham (United Kingdom)
Indications
Mupirocin (Bactroban, Centany) is a topical antibiotic produced by fermented
Pseudomonas fluorescens. It has a narrow spectrum of activity, mostly against
gram-positive aerobic bacteria (including Staphylococcus and methicillin-resistant
Staphylococcus) and many strains of Streptococcus. It is also active against some
gram-negative aerobic bacteria but is inactive against anaerobes, Chlamydia, and
fungi. It has proved equal in efficacy in the treatment of impetigo when compared
with oral erythromycin, with fewer adverse side effects.
Mupirocin does not interfere with wound healing. It is active only on topical
administration and is converted to an inert molecule on systemic administration.
Prolonged use of mupirocin increases the risk of evolution of resistant organisms.
Themechanism of action has not yet been fully classified, but it does differ from other
available antiinfective agents, and there is little chance of cross-resistance developing.
Also, unlike many other topical antibiotics, it rarely causes allergic sensitization.
Manufacturing Process
Production and recovery of Antibacterially active pseudomonic acid and
Pseudomonic acid APseudomonas fluorescens, strain NCIB 10586 was grown in submerged culture
at 30°C in a medium containing 1% corn steep liquor and 0.5% glucose in a
basic salts solution. The maximum yield of the antibiotic occurred after 24
hours and all of the detectable activity was in the culture fluid. After the
addition of barium chloride (0.5%) the cells and precipitated non-active
contaminant material were removed by centrifugation. The activity was
progressively concentrated by partitioning into isobutylmethyl ketone (IBMK)
(0.2 vol) at pH 4.5 water (0.8 vol) at pH 8.5, and then IBMK (0.25 vol) at pH
4.5 followed by evaporation to a small volume under reduced pressure. After
a further partition into water at pH 8.5 and then adjustment to pH 7-8 the
aqueous solution was freeze dried to give the sodium salt which could be
stored at 0°C for several months, without loss of activity. The antibiotic
extract was stable within the range pH 4-9 at 37°C for 24 hours. Outside
these limits rapid loss of activity occurred. The sodium salt showed a broad antibacterial spectrum against Gram positive and Gram negative bacteria,
showed low toxicity and was bacteriostatic against S. aureus (N.C.T.C. 6571)
and E. coli (M.R.E. 600).Further purification of the crude acid was effected by chromatography on
Amberlite XAD-2 polystyrene resin with a linear gradient produced by adding
0.1 N methanolic ammonia, to 0.01 N aqueous ammonia. A series of low
molecular weight acids was eluted first, followed by a fraction (30-60%
elution) that possessed the major part of the antibacterial (biological) activityPurification of Pseudomonic acid and Pseudomonic Acid AThe produced biologically active material upon methylation with diazomethane
in ether showed two spots by thin layer chromatography corresponding to
methyl pseudomonate as the major component and a minor amount of
component methyl pseudomonate-A (ratio ca 9:1 by wt.).Methyl pseudomonate was separated from methyl pseudomonate-A by
preparative layer silica gel (GF245) chromatography on development with
chloroform/isopropanol (9:1). 50% of methyl pseudomonate was recovered
from the impure residue by crystallization from benzene/petroleum ether to
give colorless needles of m.p. 76.5-78°C.Acetylation of the methyl ester with pyridine/acetic anhydride affords a
triacetate. Reduction of the methyl ester with LiAlH4 in THF afforded 1,9-
dihydroxynonanoate, m.p. 46°C.
Therapeutic Function
Antibiotic
Antimicrobial activity
It is active against staphylococci and streptococci, but also Neisseria and Haemophilus spp. Enterococcus faecalis tends to be sensitive whereas E. faecium is usually resistant. Activity against Staph. aureus is affected by inoculum such that a 10-fold increase in the inoculum causes doubling of the minimum inhibitory concentration (MIC) in vitro. Activity also decreases as pH increases above the normal skin pH of 5.5.
Acquired resistance
Before the introduction of mupirocin, resistance in Staph. aureus was uncommon, with a natural mutation frequency of 1 in 109. However, shortly after the agent was introduced, mupirocin-resistant strains began to emerge. They are of two types: low level (MIC 8–256 mg/mL) and high level (MIC >256 mg/mL).High-level resistance, in contrast, is linked to the acquisition of a transmissible resistance gene MupA that may co-transfer with other antimicrobial resistance genes. Strains that express MupA are not clinically susceptible to mupirocin.Several studies suggest that widespread use of prophylactic mupirocin may result in increased levels of resistance. In Canada increasing use of mupirocin across the country led to high-level mupirocin resistance, rising from 1.6% to 7% over a 9-year period.
Pharmaceutical Applications
Mupirocin is an antimicrobial substance originally derived from Pseudomonas fluorescens. It is a mixture of pseudomonic acids with more than 90% of the commercial product being pseudomonic acid A.It has activity predominantly against Gram-positive bacteria and its main use is as a topical agent for the eradication of carriage of methicillin-resistant Staphylococcus aureus (MRSA). It is also used as a topical treatment for superficial skin infections caused by Grampositive organisms such as impetigo.
Pharmacokinetics
Following parenteral administration, mupirocin is rapidly destroyed by non-specific esterases (possibly in renal or liver tissues since it is reasonably stable in blood) to inactive monic acid and its conjugates. It is strongly protein bound. About 0.25% is absorbed from intact skin. The skin ointment, but not the cream, contains polyethylene glycol, which may be absorbed significantly when applied to open wounds or damaged skin, including burns.
Clinical Use
Mupirocin is mainly used as a nasal cream as part of the regimen to decolonize patients who have been found to carry methicillin-resistant Staph. aureus. It can also be applied to tracheostomy, gastrostomy and other sites that are frequently colonized with MRSA.The use of mupirocin as a means of controlling outbreaks of infection due to MRSA appears to be of only marginal benefit in an endemic situation.A Cochrane Review of nine randomized controlled trials of use of mupirocin to prevent subsequent Staph. aureus infections in nasal carriers of the organism found a statistically significant reduction in such infections at any site. A small study of local therapy to reduce the risk of peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD) found that mupirocin applied three times weekly to the dialysis catheter exit site resulted in a 92% reduction in the rate of peritonitis
Veterinary Drugs and Treatments
Mupirocin is approved for treating topical infections in dogs caused by susceptible strains of Staphylococcal aureus or Staphylococcal
intermedius. It may also be of use in other species and conditions (e.g., feline acne, equine pyoderma, superficial pyoderma, interdigital
abscesses, pressure point pyodermas, etc). It also shows activity against other gram-positive pathogens: Corynebacterium sp, Clostridium
sp and Actinomyces spp.
Mupirocin is not related structurally to other commercially available antibiotics and acts by inhibiting bacterial protein synthesis
by binding to bacterial isoleucyl transfer-RNA sythetase. Its principle activity is against Gram-positive cocci (Staphylococcal spp. and
Streptococcal spp.), including beta-lactamase producing and methicillin-resistant strains. While bacterial resistance is rare, resistant
strains of Staphylococcal aureus have been identified and resistance transference is thought to be plasmid-mediated. Cross-resistance with
other antimicrobials has not been identified. Mupirocin also has activity against some Gram-negative bacteria, but is not used clinically
for infections caused by those bacteria.
Mupirocin is not significantly absorbed through the skin into the systemic circulation, but does penetrate well into granulomatous
deep pyoderma lesions and is not suitable for application to burns.
References
1) Sutherland et al. (1985), Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use; Antimicrob. Agents Chemother., 27 495
2) Rudresh et al. (2015), Prevalence of Mupirocin Resistance Among Staphylococci, its Clinical Significance and Relationship to Clinical Use; J. Lab. Physicians, 7 103
Check Digit Verification of cas no
The CAS Registry Mumber 12650-69-0 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,2,6,5 and 0 respectively; the second part has 2 digits, 6 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 12650-69:
(7*1)+(6*2)+(5*6)+(4*5)+(3*0)+(2*6)+(1*9)=90
90 % 10 = 0
So 12650-69-0 is a valid CAS Registry Number.
InChI:InChI=1/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
12650-69-0Relevant articles and documents
Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics
Gao, Shu-Shan,Wang, Luoyi,Song, Zhongshu,Hothersall, Joanne,Stevens, Elton R.,Connolly, Jack,Winn, Peter J.,Cox, Russell J.,Crump, Matthew P.,Race, Paul R.,Thomas, Christopher M.,Simpson, Thomas J.,Willis, Christine L.
, p. 3930 - 3934 (2017/03/27)
Thiomarinol and mupirocin are assembled on similar polyketide/fatty acid backbones and exhibit potent antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA). They both contain a tetrasubstituted tetrahydropyran (THP) ring that is essential for biological activity. Mupirocin is a mixture of pseudomonic acids (PAs). Isolation of the novel compound mupirocin P, which contains a 7-hydroxy-6-keto-substituted THP, from a ΔmupP strain and chemical complementation experiments confirm that the first step in the conversion of PA-B into the major product PA-A is oxidation at the C6 position. In addition, nine novel thiomarinol (TM) derivatives with different oxidation patterns decorating the central THP core were isolated after gene deletion (tmlF). These metabolites are in accord with the THP ring formation and elaboration in thiomarinol following a similar order to that found in mupirocin biosynthesis, despite the lack of some of the equivalent genes. Novel mupirocin–thiomarinol hybrids were also synthesized by mutasynthesis.
ENANTIOSPECIFIC TOTAL SYNTHESIS OF PSEUDOMONIC ACIDS FROM ARABINOSE
Fleet, G. W. J.,Gough, M. J.,Shing, T. K. M.
, p. 3661 - 3664 (2007/10/02)
The enantiospecific synthesis of pseudomonic acids from arabinose is described.
