Mupirocin Research Articles

Mupirocin W (I), a Novel Pseudomonic Acid Produced by Targeted Mutation of the Mupirocin Biosynthetic Gene Cluster.

Mupirocin W (I), a Novel Pseudomonic Acid Produced by Targeted Mutation of the Mupirocin Biosynthetic Gene Cluster.

Shift to Pseudomonic Acid B Production in P. fluorescens NCIMB10586 by Mutation of Mupirocin Tailoring Genes mupO, mupU, mupV, and macpE

Mupirocin, a polyketide-derived antibiotic from Pseudomonas fluorescens NCIMB10586, is a mixture of pseudomonic acids (PA) that target isoleucyl-tRNA synthase. The mup gene cluster encodes both type I polyketide synthases and monofunctional enzymes that should play a role during the conversion of the product of the polyketide synthase into the active antibiotic (tailoring). By in-frame deletion analysis of selected tailoring open-reading frames we show that mupQ, mupS, mupT, and mupW are essential for mupirocin production, whereas mupO, mupU, mupV, and macpE are essential for production of PA-A but not PA-B. Therefore, PA-B is not simply produced by hydroxylation of PA-A but is either a precursor of PA-A or a shunt product. In the mupW mutant, a new metabolite lacking the tetrahydropyran ring is produced, implicating mupW in oxidation of the 16-methyl group.

Mupirocin is active against methicillin-resistant Staphylococcus aureus

Mupirocin is active against methicillin-resistant Staphylococcus aureus

Tandemly Duplicated Acyl Carrier Proteins, Which Increase Polyketide Antibiotic Production, Can Apparently Function Either in Parallel or in Series

Polyketide biosynthesis involves the addition of subunits commonly derived from malonate or methylmalonate to a starter unit such as acetate. Type I polyketide synthases are multifunctional polypeptides that contain one or more modules, each of which normally contains all the enzymatic domains for a single round of extension and modification of the polyketide backbone. Acyl carrier proteins (ACP(s)) hold the extender unit to which the starter or growing chain is added. Normally there is one ACP for each ketosynthase module. However, there are an increasing number of known examples of tandemly repeated ACP domains, whose function is as yet unknown. For the doublet and triplet ACP domains in the biosynthetic pathway for the antibiotic mupirocin from Pseudomonas fluorescens NCIMB10586 we have inactivated ACP domains by inframe deletion and amino acid substitution of the active site serine. By deletion analysis each individual ACP from a cluster can provide a basic but reduced activity for the pathway. In the doublet cluster, substitution analysis indicates that the pathway may follow two parallel routes, one via each of the ACPs, thus increasing overall pathway flow. In the triplet cluster, substitution in ACP5 blocked the pathway. Thus ACP5 appears to be arranged "in series" to ACP6 and ACP7. Thus although both the doublet and triplet clusters increase antibiotic production, the mechanisms by which they do this appear to be different and depend specifically on the biosynthetic stage involved. The function of some ACPs may be determined by their location in the protein rather than absolute enzymic activity.

Mupirocin W, a novel pseudomonic acid produced by targeted mutation of the mupirocin biosynthetic gene cluster

Mutation of the mupW gene in the mupirocin biosynthetic gene cluster in Pseudomonas fluorescens results in efficient production of a novel pseudomonic acid metabolite, mupirocin W, which lacks the characteristic tetrahydropyran ring, and reveals the role of the mupW gene in pseudomonic acid biosynthesis.

New Aminoacyl-tRNA Synthetase Inhibitors as Antibacterial Agents

Increasing rates of bacterial resistance to known classes of antibiotics present a severe global challenge. As a consequence, the search for new chemical entities that address novel bacterial targets remains ongoing. Aminoacyl-tRNA synthetases (aa-RS) are essential enzymes for protein biosynthesis and emerged as an interesting target class in antibacterial research. These enzymes are present in all living organisms, and they are indispensable for the highly specific translation of the messenger-RNA (mRNA) template into protein via specific transfer-RNAs (tRNAs) as adapter molecules. When one aa-RS is inhibited, the corresponding tRNA is not charged and is therefore unavailable for translation. This leads to protein synthesis inhibition, which, in turn, causes cell growth arrest. Consequently, each compound that inhibits any of the aa-RS is a potential antibacterial agent. The clinical utility of this principle is proven by the natural product Ile-RS inhibitor pseudomonic acid, which is currently marketed as an antibacterial agent for topical application. Various chemical structures that inhibit aa-RS have been identified. These inhibitors have either been isolated from natural sources or have been generated synthetically. The synthetic inhibitors are modifications of natural inhibitors, derivatives of the natural synthetase substrates and reaction intermediates, or have been identified by screening of compound libraries. The recent progress achieved with these different classes of aa-RS inhibitors and their antibacterial potential in vitro and in vivo is discussed in this review.

Molecular epidemiology and control of nosocomial methicillin-resistant Staphylococcus aureus infection in a teaching hospital.

Nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection is difficult to control. Due to a dramatic increase in the nosocomial MRSA infection rate at our hospital from 2000 to 2001, this study was conducted to identify the source of these infections and the effectiveness of control measures. 179 healthcare workers (HCWs) were screened for carriage of MRSA. Starting in April 2001, all patients with MRSA infection or colonization were put in strict contact and cohort isolation. The bacterial isolates of HCW carriers and patients with MRSA infection from April 2001 to September 2001 were subjected to antimicrobial susceptibility testing by disk-diffusion method and molecular typing by pulsed-field gel electrophoresis (PFGE). Fifteen HCWs were found to be carriers of MRSA. They were all given topical mupirocin treatment. After these interventions, the nosocomial MRSA infection rate decreased from 1.23 to 0.53 per 1000 patient-days. All 61 MRSA isolates available for antimicrobial susceptibility testing and molecular typing were multidrug resistant. PFGE study revealed 2 predominant types, type C and type Y, comprising 36 and 12 isolates, respectively. The current study demonstrates the importance of measures to control nosocomial MRSA infections in hospitals that already have a high incidence of endemic MRSA infection. Elimination of carriage by healthcare workers, and strict contact and cohort isolation are the main effective measures.

Carriage and Transmission of MRSA

One occupational risk for healthcare workers (HCWs) is exposure to drug-resistant pathogens. For HCWs who become colonized with methicillin-resistant Staphylococcus aureus (MRSA), eradication usually involves using nasal mupirocin ointment, antiseptic solutions on skin or in hair, or -- for perineal carriers -- hexachlorophene. Researchers in Paris recently investigated MRSA …

Stringent control in the archaeal genus Sulfolobus

Six Archaea belonging to the phylum Euryarchaeota were previously analyzed with respect to stringent control. Only one of the strains studied was shown to possess Bacteria-like stringent control over stable RNA accumulation; ppGpp and pppGpp production was totally lacking in all Archaea analyzed. To broaden our knowledge of stringent control in the Archaea, we examined here the accumulation of stable RNA and the production of ppGpp and pppGpp under amino acid starvation in three species of the genus Sulfolobus belonging to the Crenarchaeota, an archaeal phylum distant from the Euryarchaeota. In these species the accumulation of sRNA was arrested when aminoacylation of tRNA was inhibited by pseudomonic acid. Furthermore, stringent control of stable RNA accumulation was relaxed by some protein synthesis inhibitors that do not interfere with aminoacylation of tRNA, a feature typical of bacterial stringent control. Neither ppGpp nor pppGpp could be detected during growth or under amino acid starvation, and the intracellular GTP levels did not decrease in the course of the stringent response. These results show that: (1) stringency is widespread in wild-type thermoacidophilic archaea; (2) in the crenarchaeal species analyzed here SC depends on the deaminoacylation of tRNA; (3) in the strains analyzed ppGpp is not produced during normal growth nor during the stringent reaction; it is therefore not an effector either of SC over sRNA synthesis or of growth control. (p)ppGpp appears to be completely absent from the Archaea and thus constitutes an additional feature that distinguishes the Bacteria from the Archaea.

Prevention of Staphylococcus aureus infections among surgical patients: Beyond traditional perioperative prophylaxis

Background Health care–related infections cause significant patient morbidity and mortality rates and add excess costs that frequently are not reimbursed. Staphylococcus aureus has long been recognized as an important pathogen in human disease and is the most common cause of nosocomial infections. Method The objective of this review of the English language literature and a MEDLINE search was to describe recent advances in the prevention of S aureus health care–related infections that are attributable to patients' endogenous colonization. The ecologic niche of S aureus is the anterior nares and nasal carriage increases the risk of the development of a surgical-site, lower respiratory tract, or bloodstream infection. S aureus carriers have a 2- to 9-fold increased risk of the development of a surgical-site or intravenous catheter infection. Results Three treatment strategies may eliminate nasal carriage: locally applied antibiotics or disinfectants, systemic antibiotics, and bacterial interference. Among these strategies, locally applied or systemic antibiotics are used most commonly. Nasal ointments or sprays and oral antibiotics have variable efficacy, and their use frequently results in antimicrobial resistance among S aureus strains. Of the commonly used agents, mupirocin (pseudomonic acid) ointment has been shown to be 97% effective in reducing S aureus nasal carriage. In a recently published randomized, double-blind, placebo-controlled trial to determine whether intranasal mupirocin reduced the rate of S aureus-infected surgical-site and other S aureus health care–related infections; 4% of S aureus nasal carriers who received mupirocin acquired S aureus health care–related infections compared with 7.7% of S aureus nasal carriers who received placebo (P = .02). The S aureus surgical-site infection rate was not reduced significantly, but carriers who received mupirocin before cardiothoracic or general surgery operations had almost 50% fewer S aureus surgical-site infections than carriers who received placebo. In this setting resistance rarely has been reported. Conclusions Given the importance of S aureus nosocomial infections and the increased risk of S aureus nasal carriage in patients with health care–related infections, investigators must study cost-effective strategies to further prevent certain types of health care–related infections or nosocomial infections that occur in specific settings. One potential strategy is to decrease or eliminate S aureus nasal carriage among certain patient populations or in certain healthcare settings.

How Does Pseudomonas fluorescens Avoid Suicide from Its Antibiotic Pseudomonic Acid?: EVIDENCE FOR TWO EVOLUTIONARILY DISTINCT ISOLEUCYL-tRNA SYNTHETASES CONFERRING SELF-DEFENSE

Two isoleucyl-tRNA synthetases (IleRSs) encoded by two distinct genes (ileS1 and ileS2) were identified in pseudomonic acid (mupirocin)-producing Pseudomonas fluorescens. The most striking difference between the two IleRSs (IleRS-R1 and IleRS-R2) is the difference in their abilities to resist pseudomonic acid. Purified IleRS-R2 showed no sensitivity to pseudomonic acid even at a concentration of 5 mm, 105 times higher than the Ki value of IleRS-R1. The amino acid sequence of IleRS-R2 exhibits eukaryotic features that are originally found in eukaryotic proteins. Escherichia coli cells transformed with the ileS2 gene exerted pseudomonic acid resistance more than did those transformed with ileS1. Cells transformed with both genes became almost as resistant as P. fluorescens. These results suggest that the presence of IleRS-R2 could be the major reason why P. fluorescens is intrinsically resistant to the antibiotic. Here we suggest that the evolutionary scenario of the eukaryotic ileS2 gene can be explained by gene acquisition and that the pseudomonic acid producer may have maintained the ileS2 gene to protect itself from pseudomonic acid.

Uso nasal de la mupirocina para Staphylococcus aureus: efecto en portadores y en infecciones nosocomiales.

Staphylococcus aureus is the agent of community-acquired and nosocomial infections. Twenty to 35% of the population permanently carries it in the nose and oropharynx, and additional 50%, carries it intermittently. Topical calcium mupirocin is an antibacterial agent against Staphylococcus aureus recommended to eradicate nasal and hand colonization in patients and health care workers. The prevalence of nasal S. aureus was determined in patients undergoing cardiovascular surgery. In addition, the effect of mupirocine on the number of carriers and rate of nosocomial infections was evaluated. An experimental prospective study was undertaken with two groups of patients: one treated with mupirocin (n = 96), and the other without treatment (n = 95). Tests for presence of nasal S. aureus and nosocomial infections were conducted in all patients. A 34% prevalence of S. aureus carriers was found. A decrease of the prevalence was found in both treated (87%) and untreated patients (33%), but in significantly different proportions (p = 0.0002, RR = 0.22, 95%CI = 0.09-0.054). This result demonstrated the effectiveness of a mupirocin treatment program to decrease numbers of nasal carriers. With regard to nosocomial infection, S. aureus prevalence was 3.6%, occurring mostly in control patients (6 of 7). Total nosocomial infection prevalence was 17.3%, evenly distributed in treated and untreated patients. This suggested that mupirocin use did not decrease the number of nosocomial infections.

Characterization of the Mupirocin Biosynthesis Gene Cluster from Pseudomonas fluorescens NCIMB 10586

The polyketide antibiotic mupirocin (pseudomonic acid) produced by Pseudomonas fluorescens NCIMB 10586 competitively inhibits bacterial isoleucyl-tRNA synthase and is useful in controlling Staphylococcus aureus, particularly methicillin-resistant Staphylococcus aureus. The 74 kb mupirocin biosynthesis cluster has been sequenced, and putative enzymatic functions of many of the open reading frames (ORFs) have been identified. The mupirocin cluster is a combination of six larger ORFs ( mmpA-F), containing several domains resembling the multifunctional proteins of polyketide synthase and fatty acid synthase type I systems, and individual genes ( mupA-X and macpA-E), some of which show similarity to type II systems ( mupB, mupD, mupG, and mupS). Gene knockout experiments demonstrated the importance of regions in mupirocin production, and complementation of the disrupted gene confirmed that the phenotypes were not due to polar effects. A model for mupirocin biosynthesis is presented based on the sequence and biochemical evidence.

Enantioselective deprotonation of meso-cycloheptanone derivative: application to the synthesis of a potential intermediate for pseudomonic acid B.

[reaction: see text] A novel synthetic path to a potential intermediate for the synthesis of pseudomonic acid B was established by employing enantioselective deprotonation of a meso-cycloheptanone derivative bearing hydroxy groups at the 3,4,5,6-positions with lithium (S,S')-alpha,alpha'-dimethyldibenzylamide as a key step.

Process improvement plan for the reduction of sternal surgical site infections among patients undergoing coronary artery bypass graft surgery

In an attempt to reduce sternal infections caused by Staphylococcus aureus , a protocol was introduced that included the administration of intranasal mupirocin calcium 2% before surgery to patients undergoing cardiothoracic surgery. Surveillance data indicated a 55% reduction in the rate of deep sternal wound infections caused by S aureus and superficial sternal wound infections have declined from 25 to 6 since the adoption of the protocol. At the study institution, this protocol is now an ongoing process to reduce the incidence of sternal infections caused by S aureus among cardiothoracic patients. (Am J Infect Control 2002;30:434-6.)

Toxic Epidermal Necrolysis Due to Administration of Celecoxib (Celebrex)

A 41-year-old woman was given celecoxib (Celebrex) for the treatment of carpal tunnel syndrome. An erythematous rash developed that progressed to exfoliative dermatitis, and the patient was diagnosed with toxic epidermal necrolysis. After transfer to the burn unit, she was treated with topical mupirocin calcium cream and bismuth tribromophenatein petrolatum gauze dressings. Her wounds healed well. This is the first case report of toxic epidermal necrolysis due to treatment with celecoxib of which we are aware.

Does Prophylactic Mupirocin Reduce Postoperative

Mupirocin, a topical antibiotic active against Staphylococcus aureus, can eliminate nasal carriage of S. aureus. Because postoperative staphylococcal

No Routine Role for Mupirocin Before Surgery

Staphylococcus aureus is a common cause of postoperative infections, especially among the 25% to 30% of the population who carry this organism in their

Mupirocin – Are We in Danger of Losing It?

Mupirocin – Are We in Danger of Losing It?

ChemInform Abstract: A Diastereocontrolled Route to the Tetrahydropyran Nucleus of Pseudomonic Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.