Purpose: Cutaneous infection in epidermolysis bullosa (EB) can cause significant morbidity, mortality, and dangerous sequelae. This review article aims to delve into the known epidemiology of EB, highlight the disease\'s primary causative agents and their antimicrobial resistance spectrum.Materials and methods: A thorough literature search was conducted using Medline, EMBASE, JBI and PubMed to gather data on the microbial landscape of EB wounds. The focus was on identifying the most common bacteria associated with EB infections and assessing their antimicrobial resistance profiles.Results: The analysis revealed that Staphylococcus aureus is the most frequently identified bacterium in EB wounds, with a notable prevalence of methicillin-resistant strains (MRSA). Specific studies on mupirocin resistance further indicated rising rates of mupirocin-resistant Staphylococcus aureus, with one study reporting rates as high as 16.07%. Additionally, high resistance to other antibiotics, such as levofloxacin and trimethoprim/sulfamethoxazole, was observed in MRSA isolates.Conclusions: The findings highlight the critical need for regular resistance surveillance and the prudent use of mupirocin to manage infections effectively in EB. The multi-drug resistant nature of pathogens in EB presents a significant challenge in treatment, highlighting the importance of antimicrobial stewardship. Ultimately, given the sparse literature and the rarity of large-scale studies, further longitudinal research on the antimicrobial resistance profile of bacteria isolated from EB wounds is essential.

Mupirocin is a broad-spectrum antibiotic that acts predominantly against Gram-positive bacteria. It is produced by Pseudomonas fluorescens NCIMB 10586 and has been clinically used to treat primary and secondary skin infections and to eradicate nasal colonisation of methicillin-resistant Staphylococcus aureus strains. Mupirocin inhibits protein synthesis by blocking the active site of isoleucyl-tRNA synthetase (IleRS), which prevents the enzyme from binding isoleucine and ATP for Ile-tRNAIle synthesis. Two types of IleRS are found in bacteria - while IleRS1 is susceptible to mupirocin inhibition, IleRS2 provides resistance to cells. These two types belong to distinct evolutionary clades which likely emerged from an early gene duplication in bacteria. Resistance in IleRS2 is based on the loss of interactions that govern mupirocin binding to IleRS1, such as hydrogen bonding to the carboxylate moiety of mupirocin. IleRS2 enzymes with Ki in the millimolar range have recently been discovered. These hyper-resistant IleRS2 variants surprisingly have a non-canonical version of the catalytic motif, which serves as a signature motif of class I aminoacyl-tRNA synthetases to which IleRS belongs. The non-canonical motif, in which the 1st and 3rd positions are swapped, is key for hyper-resistance and can be accommodated without abolishing enzyme activity in IleRS2 but not in IleRS1. Clinical use of mupirocin led to the emergence of resistance in S. aureus. Low-level resistance arises by mutations of the housekeeping IleRS1, while high-level resistance develops by the acquisition of the resistant IleRS2 on a plasmid. There is no evidence that hyper-resistant variants have been found in clinical isolates.

OBJECTIVE: Increased mupirocin use leads to mupirocin resistance and is associated with persistence of methicillin-resistant Staphylococcus aureus (MRSA) carriers, prolonged hospitalization, and significant economic burdens for health systems. The study aimed to investigate the antimicrobial activity of compounds of Salvia rosmarinus L. (\"rosemary\", formerly Rosmarinus officinalis), alone or in combination with mupirocin, against multidrug resistant MRSA using isolates obtained from pediatric patients.
METHODS: The in vitro antibacterial activity of the monoterpene α-pinene (α-Pi), a rosemary essential oil constituent, alone and in combination with mupirocin, was evaluated by determining the minimum inhibitory concentrations and minimum bactericidal concentrations (MBCs) and the fractional inhibitory concentration indices (FICIs) and fractional bactericidal concentration indices against multidrug-resistant clinical MRSA strains. The in vivo efficacy of α-Pi, alone and in combination with mupirocin, to eradicate MRSA infection was determined using an optimized mouse model of MRSA-infected wounds. Mouse skin samples (obtained via biopsy) were assessed for toxicity, and rabbit skin samples for irritation.
RESULTS: Both in vitro and in vivo, α-Pi was active against MRSA strains and acted synergistically with mupirocin against MRSA strains. Mupirocin-monoterpene combinations exhibited FICI values of 0.2 to 0.4, reducing the MBC of topical mupirocin 33-fold. A topical formulation containing α-Pi and mupirocin enhanced the efficacy of mupirocin in an in vivo MRSA-infected mouse skin model without significantly harming the skin of mice and rabbits.
CONCLUSIONS: A topical formulation combining mupirocin and α-Pi may aid in the development of innovative agents for treating MRSA infections.

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BackgroundAntimicrobial resistance to mupirocin and fusidic acid, which are used for treatment of skin infections caused by Staphylococcus aureus, is of concern.AimTo investigate resistance to fusidic acid and mupirocin in meticillin-susceptible S. aureus (MSSA) from community-acquired skin and soft tissue infections (SSTIs) in Belgium.MethodsWe collected 2013-2023 data on fusidic acid and mupirocin resistance in SSTI-associated MSSA from two large Belgian laboratories. Resistant MSSA isolates sent to the Belgian Staphylococci Reference Centre were spa-typed and analysed for the presence of the eta and etb virulence genes and the mupA resistance gene. In addition, we whole genome sequenced MSSA isolates collected between October 2021 and September 2023.ResultsMupirocin resistance increased between 2013 and 2023 from 0.5-1.5% to 1.7-5.6%. Between 2018 and 2023, 91.4% (64/70) of mupirocin-resistant isolates were co-resistant to fusidic acid. By September 2023, between 8.9% (15/168) and 10.1% (11/109) of children isolates from the two laboratories were co-resistant. Of the 33 sequenced isolates, 29 were sequence type 121, clonal and more distantly related to the European epidemic fusidic acid-resistant impetigo clone (EEFIC) observed in Belgium in 2020. These isolates carried the mupA and fusB genes conferring resistance to mupirocin and fusidic acid, respectively, and the eta and etb virulence genes.ConclusionWe highlight the spread of a mupirocin-resistant EEFIC in children, with a seasonal trend for the third quarter of the year. This is of concern because this variant is resistant to the two main topical antibiotics used to treat impetigo in Belgium.

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

BACKGROUND: Malignant pleural effusion (MPE) is a debilitating condition as it commonly causes disabling breathlessness and impairs quality of life (QoL). Indwelling pleural catheter (IPC) offers an effective alternative for the management of MPE. However, IPC-related infections remain a significant concern and there are currently no long-term strategies for their prevention. The Australasian Malignant PLeural Effusion (AMPLE)-4 trial is a multicentre randomised trial that evaluates the use of topical mupirocin prophylaxis (vs no mupirocin) to reduce catheter-related infections in patients with MPE treated with an IPC.
METHODS: A pragmatic, multi-centre, open-labelled, randomised trial. Eligible patients with MPE and an IPC will be randomised 1:1 to either regular topical mupirocin prophylaxis or no mupirocin (standard care). For the interventional arm, topical mupirocin will be applied around the IPC exit-site after each drainage, at least twice weekly. Weekly follow-up via phone calls or in person will be conducted for up to 6 months. The primary outcome is the percentage of patients who develop an IPC-related (pleural, skin, or tract) infection between the time of catheter insertion and end of follow-up period. Secondary outcomes include analyses of infection (types and episodes), hospitalisation days, health economics, adverse events, and survival. Subject to interim analyses, the trial will recruit up to 418 participants.
CONCLUSIONS: Results from this trial will determine the efficacy of mupirocin prophylaxis in patients who require IPC for MPE. It will provide data on infection rates, microbiology, and potentially infection pathways associated with IPC-related infections.
BACKGROUND: Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee has approved the study (RGS0000005920). Results will be published in peer-reviewed journals and presented at scientific conferences.
BACKGROUND: Australia New Zealand Clinical Trial Registry ACTRN12623000253606. Registered on 9 March 2023.

Nowadays, nanofibrous structures based on organic and inorganic materials are considered a drug delivery system for the controlled release of antibiotics and other antibacterial agents. The main goal of this research is a combination of the special properties of nanofibrous structure and Mupirocin-loaded Layered double hydroxide (LDH) to obtain a dual-carrier drug release system to provide long term antibacterial properties in wound healing process. Regards, unloaded layered double hydroxide (LDH) and Mupirocin-loaded LDH, which were synthesized by co-precipitation method, were added to Polyvinyl alcohol (PVA) solution in different mass ratio and electrospun using different processing conditions. The physico-chemical characterizations were performed using SEM, FTIR and tensile strength tests. The biological properties of the fabricated nanocomposites were evaluated using antibacterial test and in vitro cell culturing followed by MTT assay. The SEM results showed a bead-less and uniform morphology of nanofibrous composite containing Mupirocin(2.3 wt%)-LDH(15 wt%)/PVA with an average fiber diameter of about 270 ± 58 nm. According to the release study, the maximum release of the mupirocin drug was about 54 % in the first 6 h. The antibiogram analysis exhibited good antibacterial activity of mupirocin-loaded nanocomposite against both bacteria, especially gram-positive one. Finally, MTT assay approved the biocompatibility of the mupirocin-loaded nanocomposite. Overall, the produced nanofibrous composites would be a promising dual-carrier system for controlled release of antibiotic.

Mupirocin is a clinically important antibiotic produced by a trans-AT Type I polyketide synthase (PKS) in Pseudomonas fluorescens. The major bioactive metabolite, pseudomonic acid A (PA-A), is assembled on a tetrasubstituted tetrahydropyran (THP) core incorporating a 6-hydroxy group proposed to be introduced by α-hydroxylation of the thioester of the acyl carrier protein (ACP) bound polyketide chain. Herein, we describe an in vitro approach combining purified enzyme components, chemical synthesis, isotopic labelling, mass spectrometry and NMR in conjunction with in vivo studies leading to the first characterisation of the α-hydroxylation bimodule of the mupirocin biosynthetic pathway. These studies reveal the precise timing of hydroxylation by MupA, substrate specificity and the ACP dependency of the enzyme components that comprise this α-hydroxylation bimodule. Furthermore, using purified enzyme, it is shown that the MmpA KS0 shows relaxed substrate specificity, suggesting precise spatiotemporal control of in trans MupA recruitment in the context of the PKS. Finally, the detection of multiple intermodular MupA/ACP interactions suggests these bimodules may integrate MupA into their assembly.
Mupirocin is a clinically important polyketide antibiotic bearing a 6‐hydroxy group that is essential for biological activity. NMR spectroscopy, authentic synthetic substrates and mass spectrometry were used to establish the mechanistic steps governing incorporation of this key 6‐hydroxy group by an α‐hydroxylation bimodule that recruits a trans acting monooxygenase, MupA.

Mupirocin is a clinically important antibiotic produced by Pseudomonas fluorescens NCIMB 10586 that is assembled by a complex trans-AT polyketide synthase. The polyketide fragment, monic acid, is esterified by a 9-hydroxynonanoic acid (9HN) side chain which is essential for biological activity. The ester side chain assembly is initialised from a 3-hydroxypropionate (3HP) starter unit attached to the acyl carrier protein (ACP) MacpD, but the fate of this species is unknown. Herein we report the application of NMR spectroscopy, mass spectrometry, chemical probes and in vitro assays to establish the remaining steps of 9HN biosynthesis. These investigations reveal a complex interplay between a novel iterative or \"stuttering\" KS-AT didomain (MmpF), the multidomain module MmpB and multiple ACPs. This work has important implications for understanding the late-stage biosynthetic steps of mupirocin and will be important for future engineering of related trans-AT biosynthetic pathways (e.g. thiomarinol).
Mupirocin is a clinically important antibiotic in which the polyketide fragment, monic acid, is esterified to a 9‐hydroxynonanoic acid (9HN) side chain, which is essential for biological activity. NMR spectroscopy, mass spectrometry, chemical probes and in vitro assays were used to establish how 9HN is assembled through the action of multiple acyl carrier proteins, two ketosynthases and fatty acid β‐keto processing enzymes.