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Severe cutaneous injuries may not heal spontaneously and may necessitate the use of supplementary therapeutic methods. Electrospun nanofibers possess high porosity and specific surface area, which provide the necessary microenvironment for wound healing. Here in, the nanofibers of Soluplus-soy protein isolate (Sol-SPI) containing mupirocin (Mp) were fabricated via electrospinning for wound treatment. The fabricated nanofibers exhibited water absorption capacities of about 300.83 ± 29.72% and water vapor permeability values of about 821.8 ± 49.12 g/m 2 day. The Sol/SPI/Mp nanofibers showed an in vitro degradability of 33.73 ± 3.55% after 5 days. The ultimate tensile strength, elastic modulus, and elongation of the Sol/SPI/Mp nanofibers were measured as 3.61 ± 0.29 MPa, 39.15 ± 5.08 MPa, and 59.11 ± 1.94%, respectively. Additionally, 85.90 ± 6.02% of Mp loaded in the nanofibers was released in 5 days in vitro, and by applying the Mp-loaded nanofibers, 93.06 ± 5.40% and 90.40 ± 5.66% of S. aureus and E. coli bacteria were killed, respectively. Human keratinocyte cells (HaCat) demonstrated notable biocompatibility with the prepared nanofibers. Furthermore, compare to other groups, Sol-SPI-Mp nanofibers caused the fastest re-epithelialization and wound healing in a rat model. The findings of this study present a novel nanofiber-based wound dressing that accelerates the healing of severe skin wounds with the risk of infection., (© 2024. The Author(s).)

Despite substantial advancements in wound dressing development, effective skin repair remains a significant challenge, largely due to the persistent issue of recurrent infections. Three-dimensional printed constructs that integrate bioactive and antibacterial agents hold significant potential to address this challenge. In this study, a 3D-printed hydrogel scaffold composed of polyallylamine hydrochloride (PAH) and pectin (Pc), incorporated with mupirocin (Mp)-loaded quaternized chitosan nanoparticles (QC NPs) was fabricated. The primary objective of this study was to facilitate a controlled and sustained release of Mp via the QC NPs. The average size of QC-Mp nanoparticles was measured to be 66.05 nm and the average strand diameter and pore size of the 3D-printed construct were measured as 147.22 ± 5.83 and 388.44 ± 14.50 μm, respectively. The hemolysis rate of all scaffolds was below 2 %, indicating that they can be classified as non-hemolytic materials with sufficient blood compatibility. The PAH-Pc/QC-Mp scaffold exhibited significant antibacterial activity, enhanced cell viability in HaCat cells, sustained Mp release until day 7 (⁓60 %), and in-vivo wound healing promotion by stimulation of human keratinocytes. In conclusion, the proposed biocompatible construct demonstrates significant potential for the treatment of chronic and infected wounds by preventing infection and promoting accelerated wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chitosan-based biomaterials are being investigated for their unique properties that support skin regeneration and wound healing. This study focused on the preparation and characterization of a mupirocin (Mup)-loaded PEGylated chitosan (CS-PEG) nanoparticulate film (NF) [CBNF]. The CBNF was characterized using FTIR spectroscopy and SEM analysis. The results demonstrated that CBNF was successfully incorporated into the composites, as shown by functional group modification through FTIR analysis. Additionally, the SEM micrograph revealed the deposition of nanoparticles (<200 nm) on the surface of transparent CBNF. The film has higher water absorption (≥1700%) and moderate water retention ability within 6 h. Furthermore, histological findings showed significant development, with re-epithelialization and granulation of tissues after 19 days, indicating the healing efficiency of CNBF. These results suggest that drug-loaded films could be an effective carrier and delivery agent for Mup-like anti-inflammatory drugs.

Objectives: To characterize the mobile genetic elements and genetic localization of ileS2 in high-level mupirocin-resistant (Hi-MupR) methicillin-resistant Staphylococcus pseudintermedius (MRSP) and MRSA isolates recovered from canine and feline clinical samples., Methods: The identification of bacterial species and presence of mecA and ileS2 genes in MRSP and MRSA isolates were performed using MALDI-TOF MS and PCR, respectively. Antimicrobial resistance (AMR) phenotypes were determined by broth microdilution assays. The genome characteristics, ileS2-containing elements and staphylococcal cassette chromosome mec (SCCmec) were illustrated using complete circular genomes obtained from hybrid assembly of Illumina short-reads and Oxford Nanopore Technologies long-reads. These were analysed through phylogenetic and bioinformatics approaches., Results: A total of 18 MRSP clinical isolates and four MRSA clinical isolates exhibited the Hi-MupR phenotype and carried multiple AMR genes, including mecA and ileS2 genes. MRSP ST182-SCCmec V (n = 6) and ST282-ΨSCCmec57395-t10 (n = 4) contained the ileS2 transposable unit associated with IS257 on the chromosome. Three MRSA ST398-SCCmec V-t034/t4652 isolates carried ∼42 kb pSK41-like ileS2 plasmids, whereas similar ileS2 plasmids lacking tra genes were found in MRSP ST282-ΨSCCmec57395-t72/t21 isolates. Furthermore, a new group of ileS2 plasmids, carried by MRSP ST45-ΨSCCmec57395, ST433-ΨSCCmecKW21-t05 and ST2165-SCCmec IV-t06, and by one MRSA ST398-SCCmec V-t034 strain, shared the plasmid backbone with the cfr/fexA-carrying plasmid pM084526&#95;1 in MRSA ST398., Conclusions: This study provides the first evidence of ileS2 integration into the S. pseudintermedius chromosome, which is a rare occurrence in staphylococcal species, and plasmids played a pivotal role in dissemination of ileS2 in both staphylococcal species., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

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.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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.

An impermeable outer membrane and multidrug efflux pumps work in concert to provide Gram-negative bacteria with intrinsic resistance against many antibiotics. These resistance mechanisms reduce the intracellular concentrations of antibiotics and render them ineffective. The natural product thiomarinol A combines holothin, a dithiolopyrrolone antibiotic, with marinolic acid A, a close analogue of mupirocin. The hybridity of thiomarinol A converts the mupirocin scaffold from inhibiting Gram-positive bacteria to inhibiting both Gram-positive and -negative bacteria. We found that thiomarinol A accumulates significantly more than mupirocin within the Gram-negative bacterium Escherichia coli , likely contributing to its broad-spectrum activity. Antibiotic susceptibility testing of E. coli mutants reveals that thiomarinol A overcomes the intrinsic resistance mechanisms that render mupirocin inactive. Structure-activity relationship studies suggest that the dithiolopyrrolone is a privileged moiety for improving the accumulation and antibiotic activity of the mupirocin scaffold without compromising binding to isoleucyl-tRNA synthetase. These studies also highlight that accumulation is required but not sufficient for antibiotic activity. Our work reveals a role of the dithiolopyrrolone moiety in overcoming intrinsic mupirocin resistance in E. coli and provides a starting point for designing dual-acting and high-accumulating hybrid antibiotics.

In the current study, a core-shell nanofibrous wound dressing based on Pluronic-F127 (F127) containing 2 wt% mupirocin (Mup) core and pectin (Pec)-keratin (Kr) shell was fabricated through coaxial electrospinning technique, and the blended nanofibers were also fabricated from the same materials. The fiber diameter and specific surface area of the blended nanofibers were about 101.56 nm and 20.16 m 2 /g, while for core-shell nanofibers they were about 97.32 nm and 25.26 m 2 /g, respectively. The resultant blended and core-shell nanofibers experienced a degradation of 27.65 % and 32.28 % during 7 days, respectively. The drug release profile of core-shell nanofibers revealed a sustained release of Mup over 7 days (87.66 %), while the blended F127-Pec-Kr-Mup nanofibers had a burst release within the first few hours (89.38 % up to 48 h) and a cumulative release of 91.36 % after 7 days. Due to the controlled release of Mup, the core-shell structure significantly improved the human keratinocytes behavior, angiogenic potential and wound healing in a rat model compared to the blended structure. In conclusion, the F127-Mup/Pec-Kr core-shell nanofibrous wound dressing appears to be a promising candidate for the prevention of infection, and can potentially accelerate the recovery and healing of chronic and ischemic wounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The pathogenicity of Staphylococcus epidermidis is largely attributed to its exceptional ability to form biofilms. Here, we report that mupirocin, an antimicrobial agent widely used for staphylococcal decolonization and anti-infection, strongly stimulates the biofilm formation of S. epidermidis. Although the polysaccharide intercellular adhesin (PIA) production was unaffected, mupirocin significantly facilitated extracellular DNA (eDNA) release by accelerating autolysis, thereby positively triggering cell surface attachment and intercellular agglomeration during biofilm development. Mechanistically, mupirocin regulated the expression of genes encoding for the autolysin AtlE as well as the programmed cell death system CidA-LrgAB. Critically, through gene knockout, we found out that deletion of atlE, but not cidA or lrgA, abolished the enhancement of biofilm formation and eDNA release in response to mupirocin treatment, indicating that atlE is required for this effect. In Triton X-100 induced autolysis assay, mupirocin treated atlE mutant displayed a slower autolysis rate compared with the wild-type strain and complementary strain. Therefore, we concluded that subinhibitory concentrations of mupirocin enhance the biofilm formation of S. epidermidis in an atlE dependent manner. This induction effect could conceivably be responsible for some of the more unfavourable outcomes of infectious diseases., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Treatment of contaminated wounds represents a significant challenge in healthcare and there is a need to develop approaches maximising skin retention to maintain therapeutic concentrations of anti-infectives at the wound site. The objective of the present study was to develop and evaluate mupirocin calcium nanolipid emulgels to enhance wound healing performance and patient acceptability., Methods: Nanostructured lipid carriers (NLCs) of mupirocin calcium were prepared by the phase inversion temperature method using Precirol ATO 5 (Gattefosse, India) and oleic acid as lipids and Kolliphor RH 40 (BASF, India) as surfactant and further incorporated into a gel base for topical delivery., Results: The particle size, polydispersity index and zeta potential of mupirocin NLCs were found to be 128.8±1.25nm, 0.283±0.003 and -24.2±0.56mV, respectively. In vitro release studies from developed emulgel showed sustained drug release over 24 hours. Ex vivo drug permeation studies through excised rat abdominal skin showed better skin permeation (1712.38±15. 57μg/cm 2 ) from developed emulgel compared to marketed ointment (827.92±21.42μg/cm 2 ) after 8 hours, which was in agreement with in vitro antibacterial activity. Studies on Wistar rats indicated the nonirritant potential of developed emulgels. Further, mupirocin emulgels showed improved efficacy in percent wound contraction of acute contaminated open wounds in Wistar rats using a full-thickness excision wound healing model., Conclusion: The emulgels of mupirocin calcium NLCs appear to be effective in the treatment of contaminated wounds due to increased skin deposition and sustained release, thereby enhancing the wound healing potential of existing molecules.

Objective: To assess the incidence rate of S. aureus colonization at baseline along with the mupirocin susceptibility (or resistance) rate in patients in a neonatal intensive care unit (NICU) and a pediatric intensive care unit (PICU) in conjunction with the implementation of universal decolonization as the standard of care., Design: Prospective cohort study., Setting: Children's Hospital of Michigan (CHM) inpatient intensive care units (ICUs)., Participants: Newly admitted pediatric patients to the CHM NICU or PICU aged between 1 day and ≤21 years., Interventions: Baseline and follow-up S. aureus screening cultures were obtained before patients underwent universal decolonization with mupirocin 2% antibiotic ointment (intranasal and umbilical) and chlorhexidine baths as standard of care to reduce CLABSI rates., Results: Baseline S. aureus colonization rates of new admissions to the CHM NICU and PICU were high at 32% and 29%, respectively. Baseline mupirocin susceptibility to any S. aureus growth was 98.4%. All baseline culture isolates whether positive for MRSA or MSSA, with one exception, had minimum inhibitory concentrations (MICs) of ≤0.19 µg/mL. All follow-up study cultures after universal decolonization at 7 days or beyond with any S. aureus growth had mupirocin MICs of ≤0.125 µg/mL., Conclusions: Baseline S. aureus colonization rates of new admissions to the CHM ICUs were high as was baseline mupirocin susceptibility. Follow-up cultures, albeit limited in number, did not detect increasing mupirocin MICs over 1 year, despite broad mupirocin exposure due to the implementation of universal decolonization.

The utilization of poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) with entrapped fish oil (FO) loaded in collagen-based scaffolds for cutaneous wound healing using a porcine model is unique for the present study. Full-depth cutaneous excisions (5 × 5 cm) on the pig dorsa were treated with pure collagen scaffold (control, C), empty PLGA NPs (NP), FO, mupirocin (MUP), PLGA NPs with entrapped FO (NP/FO) and PLGA NPs with entrapped MUP (NP/MUP). The following markers were evaluated on days 0, 3, 7, 14 and 21 post-excision: collagen, hydroxyproline (HP), angiogenesis and expressions of the COX2, EGF, COL1A1, COL1A3, TGFB1, VEGFA, CCL5 and CCR5 genes. The hypothesis that NP/FO treatment is superior to FO alone and that it is comparable to NP/MUP was tested. NP/FO treatment increased HP in comparison with both FO alone and NP/MUP (day 14) but decreased (p < 0.05) angiogenesis in comparison with FO alone (day 3). NP/FO increased (p < 0.05) the expression of the CCR5 gene (day 3) and tended (p > 0.05) to increase the expressions of the EGF (day 7, day 14), TGFB1 (day 21) and CCL5 (day 7, day 21) genes as compared with NP/MUP. NP/FO can be suggested as a suitable alternative to NP/MUP in cutaneous wound treatment.

We describe the identification of a methicillin-resistant, high-level mupirocin-resistant Staphylococcus argenteus . The isolate (1801221) was characterized as t6675-ST2250-SCC mec IVc, and whole-genome sequencing revealed that the isolate possessed two plasmids. One plasmid (34,870 bp), designated p1&#95;1801221 with rep23 , harboured the mupirocin resistance ( mupA ) gene. The second plasmid (20,644 bp), assigned as p2&#95;1801221 with rep5a and rep16 , carried the resistance determinants for penicillin ( blaZ ) and cadmium ( cadD ). Phylogenetic analysis revealed that the isolate clustered with the European ST2250 lineage. The overall high similarity of both plasmids in S. argenteus with published DNA sequences of Staphylococcus aureus plasmids strongly suggests an interspecies transfer. The pathogenic potential, community and nosocomial spread, and acquisition of antibiotic resistance gene determinants, including the mupA gene by S. argenteus , highlight its clinical significance and the need for its correct identification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shittu, Layer-Nicolaou, Strommenger, Nguyen, Bletz, Mellmann and Schaumburg.)

This study reports the formulation of mupirocin-loaded chitosan microspheres embedded in Piper betle extract containing collagen scaffold as combinational drug delivery for improved wound healing. Selection of chitosan type (molecular weight and degree of deacetylation) was carried out based on their antibacterial efficacy. The low molecular weight chitosan was selected owing to the highest antibacterial action against gram-positive as well as gram-negative bacteria. Low molecular weight chitosan-microspheres showed spherical shape with largely smooth surface morphology, 11.81% of mupirocin loading, and its controlled release profile. The XRD, DSC thermograms, and FT-IR spectral analysis revealed the mupirocin loaded in molecularly dispersed or in amorphous form, and having no chemical interactions with the chitosan matrix, respectively. The in vivo study indicates potential effect of the mupirocin, Piper betle, and chitosan in the collagen scaffold in the wound healing efficiency with approximately 90% wound healing observed at the end of 15 days of study for combinational drug-loaded chitosan microspheres-collagen scaffold-treated group. The histopathology examination further revealed tissue lined by stratified squamous epithelium, collagen deposition, fibroblastic proliferation, and absence of inflammation indicating relatively efficient wound healing once treated with combinational drug-loaded chitosan microspheres containing scaffold., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The development of new antimicrobial drugs is critically needed due to the alarming increase in antibiotic resistance in bacterial pathogens. The active sites of different bacterial aminoacyl tRNA synthetases (aaRS) are validated targets of antibiotics. At present, the only aaRS inhibitor approved is mupirocin (MRC) which targets bacterial isoleucyl tRNA synthetase (IleRS). The present work is aimed at understanding the lacunae of knowledge concerning the active site conformational dynamics in IleRS in the presence of inhibitor mupirocin. With this end in view, we have carried out classical molecular dynamics simulation and metadynamics simulations of the open state of IleRS from Staphylococcus aureus ( Sa IleRS), the closed state tripartite complex bound with cognate adenylate (Ile-AMP) and tRNA, the closed state tripartite complex bound with noncognate MRC, and the closed state tripartite complex bound with tRNA and MRC with mutated Sa IleRS (V588F). The present simulation established a dynamic picture of Sa IleRS complexed with cognate and the noncognate substrates which are completely consistent with crystallographic and biochemical studies and explain the existing lacunae of knowledge. The active site is significantly more compact in the Ile-AMP bound complex compared to the open state due to the closure of the KMSKS and HMGH loops and clamping down of the tRNA acceptor end near the active site gate. The present result shows that the unusual open conformational state of the KMSKS loop observed in the cognate substrate-bound complex in the crystal is due to crystallographic constraints. Although the mupirocin tightly fits the catalytic active site in the MRC-bound complex, the nonanoic acid moiety is partly exposed to the water. The KMSKS loop is pushed open in the MRC-bound complex to accommodate the noncognate MRC. New tunnels open up, extending to the editing site in the complex. Out of its three broad segments, the C12 to C17 segment, the conjugated segment, and the nonanoic moiety, the conjugated part of MRC binds most effectively with the active site of the MRC-bound complex. The aromatic residues packing around the C12 to C17 segment of MRC stabilize the tRNA hairpin conformation in a similar way as observed in the TrpRS. The V588F mutation is weakening the interaction between this region of the active site and weakens the binding of MRC in the active site. This result explains why the V588F mutation is responsible for low-level mupirocin resistance. The free energy of unbinding the conjugated segment (and C12 to C17 segment, as well) largely contributes to the total free energy of unbinding the MRC. The active site organization of IleRS from eukaryotic Candida albicans is compared with the bacterial IleRS active site to understand the low binding affinity in eukaryotic IleRS. The present study could be a starting point of future studies related to the development of effective drug binding in the Sa IleRS.

Hybrid antibiotics are an emerging antimicrobial strategy to overcome antibiotic resistance. The natural product thiomarinol A is a hybrid of two antibiotics: holothin, a dithiolopyrrolone (DTP), and marinolic acid, a close analogue of the drug mupirocin that is used to treat methicillin-resistant Staphylococcus aureus (MRSA). DTPs disrupt metal homeostasis by chelating metal ions in cells, whereas mupirocin targets the essential enzyme isoleucyl-tRNA synthetase (IleRS). Thiomarinol A is over 100-fold more potent than mupirocin against mupirocin-sensitive MRSA; however, its mode of action has been unknown. We show that thiomarinol A targets IleRS. A knockdown of the IleRS-encoding gene, ileS , exhibited sensitivity to a synthetic analogue of thiomarinol A in a chemical genomics screen. Thiomarinol A inhibits MRSA IleRS with a picomolar K and binds to IleRS with low femtomolar affinity, 1600 times more tightly than mupirocin. We find that thiomarinol A remains effective against high-level mupirocin-resistant MRSA and provide evidence to support a dual mode of action for thiomarinol A that may include both IleRS inhibition and metal chelation. We demonstrate that MRSA develops resistance to thiomarinol A to a substantially lesser degree than mupirocin and the potent activity of thiomarinol A requires hybridity between DTP and mupirocin. Our findings identify a mode of action of a natural hybrid antibiotic and demonstrate the potential of hybrid antibiotics to combat antibiotic resistance.i and binds to IleRS with low femtomolar affinity, 1600 times more tightly than mupirocin. We find that thiomarinol A remains effective against high-level mupirocin-resistant MRSA and provide evidence to support a dual mode of action for thiomarinol A that may include both IleRS inhibition and metal chelation. We demonstrate that MRSA develops resistance to thiomarinol A to a substantially lesser degree than mupirocin and the potent activity of thiomarinol A requires hybridity between DTP and mupirocin. Our findings identify a mode of action of a natural hybrid antibiotic and demonstrate the potential of hybrid antibiotics to combat antibiotic resistance.

High-level mupirocin resistance (HLMR) is determined by the plasmid-located ileS2 gene flanked by two copies of the insertion sequence 257 (IS257). The molecular epidemiology of high-level mupirocin-resistant isolates could be assessed by the determination of their IS257-ileS2 spacer regions conformation. In this study, 188 isolates of methicillin-resistant staphylococci were subjected to the detection of HLMR, and analysis of the conformation of the IS257-ileS2 spacer regions. Mupirocin resistance was detected in five (2,6%) isolates, among which two were recognized as Staphylococcus pseudintermedius, two as Staphylococcus haemolyticus, and one as Staphylococcus aureus. High-level mupirocin resistance was revealed by the agar disk diffusion method, and MIC values, and was confirmed by the detection of the ileS2 gene. The conformations of the IS257-ileS2 spacer regions were homologous in two S. haemolyticus strains tested. The remaining three isolates showed diverse IS257-ileS2 conformations. The results of this study indicate that HLMR occasionally occurs in staphylococci isolated from companion animals. The heterogeneity and the homogeneity of the IS257-ileS2 spacer regions confirm that the ileS2 gene spread among staphylococci of animal origin by the transfer of different as well as the same plasmids. Surveillance of the occurrence of mupirocin resistance and molecular characterization of resistant isolates are strongly recommended due to the possibility of plasmid-located resistance gene transfer between staphylococci., (Copyright © 2021. Published by Elsevier B.V.)

Background: Staphylococcus aureus causes various infections, including skin and soft tissue infections (SSTIs). In this study, methicillin-susceptible S. aureus (MSSA) from SSTIs among patients in three tertiary-care hospitals in Greece were studied in terms of antimicrobial resistance, clonal distribution, toxin and adhesin genes carriage., Results: During a five-year period (2014-2018), 6145 S. aureus were recovered from 13,244 patients with SSTIs and tested for antimicrobial susceptibility. MSSA were 4806 (78.21 %) including 1484 isolates with mupirocin minimum inhibitory concentration (MIC) > 64 mg/L (30.88 %). Two hundred and sixty representative mupirocin-resistant MSSA were analyzed for genes encoding Panton-Valentine leukocidin (PVL, lukS/lukF-PV), exfoliative toxins (eta, etb), adhesin FnbA (fnbA) and resistance genes mupA (high-level resistance to mupirocin), fusB (fusidic acid), aminoglycosides' modifying enzymes, ermA, ermC and msrA (macrolides/lincosamides) by PCRs. Strains were classified into clones by PFGE and MLST. All mupirocin-resistant MSSA were penicillin-resistant; 92.7 % expressed resistance to fusidic acid and 88.9 % to tobramycin. All 260 molecularly analyzed isolates were mupA-positive; all fusidic acid-resistant (241/260) carried fusB whereas, the tobramycin-resistant ones (230), ant(4')-Ia. The majority carried eta (93.85 %), etb (98.08 %) and fnbA (88.85 %). PFGE typing revealed a mostly unvarying population; 260 MSSA were grouped into three types. One major eta/etb-positive clone comprising of 258/260 strains (99.2 %), PFGE type 1, was classified as ST121, including nine strains co-carrying PVL. Another PVL-positive strain was identified as ST1, and one toxins-negative as ST21., Conclusions: A mupirocin-resistant MSSA clone, ST121, carrying resistance, exfoliative toxins and adhesin genes, was spread and predominated in SSTIs from patients in Greece during the five-year studied period.

Retapamulin activity against 53 isolates obtained from a mupirocin-resistant community-acquired methicillin-resistant Staphylococcus aureus pediatric disease cluster was evaluated using broth microdilution. All strains were susceptible to retapamulin with minimum inhibitory concentrations ≤ 0.5 μg/mL. DNA sequence analysis of rplC and cfr identified one rplC strain variant that did not demonstrate reduced phenotypic susceptibility to retapamulin. These results demonstrate that retapamulin may be a useful alternative therapy for mupirocin-resistant community-acquired methicillin-resistant S. aureus, especially in disease clusters., Competing Interests: J.L. and this work was supported by a grant from KiDS of New York University Foundation and from the generous donation of Judith and Irwin Kallman. B.S. is supported by the National Institutes of Health grants (R01 AI103268) and NIAID HHS (N272201400019C). A.P. and J.L. have received research grant funding from Aqua Pharmaceuticals. A.J.R. has acted as a consultant for Pfizer and served on an advisory board for Janssen, outside the scope of this work. B.S. has served on an advisory board for MicroGen diagnostics, outside the scope of this work. A donation from the Kallman family supported this work. B.S. is supported by the National Institutes of Health grants R01AI137336-01A1 and R01AI140754-01A1. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To characterize the microbial communities of the anterior nares (nose) and posterior pharynx (throat) of adults dwelling in the community and in nursing homes before and after treatment with intranasal mupirocin., Methods: Staphylococcus aureus-colonized adults were recruited from the community (n = 25) and from nursing homes (n = 7). S. aureus colonization was confirmed using cultures. Participants had specimens taken from nose and throat for S. aureus quantitation using quantitative PCR for the nuc gene and bacterial profiling using 16S rRNA gene sequencing over 12 weeks. After two baseline study visits 4 weeks apart, participants received intranasal mupirocin for 5 days with 3 further visits over a 8 week follow-up period., Results: We found a decrease in the absolute abundance of S. aureus in the nose for 8 weeks after mupirocin (1693 vs 141 fg/ul, p = 0.047). Mupirocin caused a statistically significant disruption in bacterial communities of the nose and throat after 1 week, which was no longer detected after 8 weeks. Bacterial community profiling demonstrated that there was a decrease in the relative abundance of S. aureus (8% vs 0.3%, p<0.01) 8 weeks after mupirocin and a transient decrease in the relative abundance of Staphylococcus epidermidis in the nose (21% vs 5%, p<0.01) 1 week after mupirocin., Conclusions: Decolonization with mupirocin leads to a sustained effect on absolute and relative abundance of S. aureus but not for other bacteria in the nose. This demonstrates that a short course of mupirocin selectively decreases S. aureus in the nose for up to 8 weeks., Competing Interests: The authors have declared that no competing interests exist.

Staphylococcus aureus (S.aureus) is both a colonizer as well as a human pathogen that causes a variety of diseases. Mupirocin is a topical antimicrobial agent which is very effective against S.aureus infection. However, treating the S.aureus infection using mupirocin could be complicated due to biofilm formation. Consequently, resistance to mupirocin occurs and leads to chronic infection. The combination of mupirocin with a compound that has biofilm eradicating effect would be an ideal solution for effectively treating biofilm infections. Therefore, in this study, we have investigated the biofilm inhibitory and eradication effect of mupirocin with three essential oils (Cinnamon Oil (CO), Eugenol (EU) and Eucalyptus Oil (EO)) against sessile S.aureus. From these preliminary results, it was found that the mupirocin-CO (0.2 µg/ml-5.218 mg/ml) combination has a better synergistic antibiofilm effect against sessile S.aureus and the fractional inhibitory concentration index was found to be 0.458. The best combination of mupirocin with CO was loaded into a non-greasy O/W cream. The physico-chemical and microbiological evaluations were carried out for the prepared cream. The prepared cream has better biofilm eradication activity (40%) when compared to a marketed cream (20%).

Despite the widespread use of chlorhexidine (CHX) to prevent infection, data regarding the in vitro action of CHX against methicillin-resistant Staphylococcus aureus (MRSA) are limited. Clinical isolates from Hospital das Clinicas, Sao Paulo, Brazil, identified during 2002/2003 and 2012/2013 were studied to describe the susceptibility to CHX and mupirocin, molecular characteristics, and virulence profile of MRSA. Susceptibility test to Mupirocin was performed by the disk diffusion method and to CHX by the agar dilution technique. PCR for virulence genes, mecA gene and Staphylococcal Cassette Chromosome mec (SCCmec) types were investigated as well. Mupirocin- and CHX-resistant isolates were sequenced using the IlluminaTM plataform. Two hundred and sixteen MRSA clinical isolates were evaluated: 154 from infected and 62 from colonized patients. Resistance to mupirocin was observed in four isolates assigned as SCCmec type III and STs (ST05; ST239 and ST105) carrying mupA and blaZ, two of them co-harboring the ileS gene. Only one isolate assigned as SCCmec type III was resistant to CHX (MIC of 8.0 μg.mL-1) and harbored the qacA gene. Resistance to chlorhexidine and mupirocin were found in isolates carrying qacA and mupA in our hospital. Since these genes are plasmid-mediated, this finding draws attention to the potential spread of resistance to mupirocin in our hospital.

Importance: Chlorhexidine gluconate (CHG) and mupirocin are widely used to decolonize patients with methicillin-resistant Staphylococcus aureus (MRSA) and reduce risks associated with infection in hospitalized populations. Quantifying the association of an application of CHG alone or in combination with mupirocin with risk of MRSA infection is important for studies evaluating alternative decolonization strategies or schedules and for identifying whether there is room for improved decolonizing agents., Objective: To estimate the proportion of patients with MRSA decolonized per application of CHG and mupirocin from existing population-level studies., Design, Setting, and Participants: A stochastic mathematical model of an 18-bed intensive care unit (ICU) in an academic medical center operating over 1 year was used to estimate parameters for the proportion of simulated patients with MRSA decolonized per application of CHG and mupirocin. The model was conducted using approximate bayesian computation with data from an existing meta-analysis of studies conducted from February 2005 through January 2015. Data were analyzed from January 2018 through November 2019., Exposure: A universal decolonization protocol for colonized patients in the ICU using CHG or CHG and mupirocin in combination was simulated., Main Outcomes and Measures: The proportion of patients with MRSA decolonized per application of CHG and mupirocin was estimated., Results: The estimated proportion of patients with MRSA decolonized per application of CHG was 0.15 (95% credible interval, 0.01-0.42), and the estimated proportion per application of mupirocin in conjunction with CHG was 0.15 (95% credible interval, 0.01-0.54). A lag in colonization detection was associated with decreases in the CHG estimate (0.11; 95% credible interval, 0.01-0.30) and mupirocin estimate (0.10; 95% credible interval, 0.00-0.34), which were sensitive to the value of the modeled contact rate between nurses and patients. A 1% increase in the value of this parameter was associated with a 0.73% increase in the estimated combined outcomes associated with CHG and mupirocin (95% CI: 0.71, 0.75). Gaps longer than 24 hours in the administration of decolonizing agents were associated with a decrease of within-ICU MRSA transmission. Compared with a mean (SD) of 1.23 (0.27) acquisitions per 1000 patient-days in scenarios with no decolonizing bathing, a bathing protocol administering CHG and mupirocin every 120 hours was associated with a mean (SD) acquisition rate of 1.03 (0.24) acquisitions per 1000 patient days, a 16.3% decrease (95% CI, 14.7%-18.0%; P > .001)., Conclusions and Relevance: These findings suggest that there may be room for significant improvement in anti-MRSA disinfectants, including the compounds themselves and their delivery mechanisms. Despite the decolonization estimates found in this study, these agents are associated with robust outcomes after delays in administration, which may help in alleviating concerns over patient comfort and toxic effects.

Objectives: To investigate the genetic characteristics associated with eradication failure of Staphylococcus aureus in infants below 90 days old., Methods: S. aureus isolated from clinical specimen cultures (blood, surgical tissue, or drainage, pus, etc.) and routine screening cultures in the neonatal intensive care unit (nasal and axillary skin swab) from patients below 90 days old were collected prospectively for 1 year, from August 2017 to July 2018. The isolates underwent typing and screening for genes associated with chlorhexidine (qacA/B), quaternary ammonium (smr), and mupirocin resistance (iles mutation, mupA, mupB), as well as Panton-Valentine leukocidin (PVL) toxin., Results: During the study period, 40 nonduplicate isolates were included for analyses, of which 70.0% were methicillin-resistant S. aureus (MRSA). Mupirocin resistance was found in 25% of the total isolates; 17.4% of the colonizers; and 35.3% of the pathogens (P = 0.196). Chlorhexidine resistance gene was found in 3 MRSA isolates colonized in the nares of preterm infants. All isolates harbored the disinfectant quaternary ammonium compound (QAC) resistance gene. PVL toxin gene was found in 57.5%, and the presence of PVL gene among colonizers and pathogens was similar (69.6% vs. 41.2%, P = 0.072)., Conclusions: Mupirocin, chlorhexidine, and QAC-resistant MRSAs harboring the PVL toxin gene were found in the nasal carriages of preterm infants. In this highly vulnerable patient population, one-fourth of the isolates harbored mupirocin-resistant genes, and all were resistant to QAC disinfectants. These strains are associated with persistence in both carriage and environmental reservoirs within the hospitals.

Methicillin-resistant Staphylococcus aureus (MRSA) decolonization is an effective measure to prevent clinical infection but resistance is a concern. We aim to evaluate the impact of mupirocin (MUP) ointment formulary removal, plateauing use of chlorhexidine gluconate (CHG), and hospital-wide introduction of octenidine (OCT)-based products on the minimum inhibitory concentration (MIC) of MRSA to MUP, CHG, and OCT in our hospital. A prevalence study was conducted at three time points (TP) on consecutive MRSA screening isolates to evaluate for their MICs to MUP, CHG, and OCT using broth microdilution sensititre plates and detection of the ileS-2 gene encoding high-level MUP resistance in 2013 (pre-intervention TP1; n = 160), 2016 (early post-intervention TP2; n = 99) and 2017 (late post-intervention TP3; n = 76). Statistical analyses were performed using Chi square test with reference from TP1. There was a significant improvement in MUP susceptibility (MIC < 4 mcg/ml) from 71.9% (TP1) to 86.9% (TP2; p = 0.006) to 88.2% (TP3; p = 0.007). The prevalence of MUP high-level resistance (MIC > 256 mcg/ml) reduced from 25.0% (TP1) to 12.1% (TP2; p = 0.014) to 5.3% (TP3; p = 0.001). Likewise, the prevalence of isolates harboring the ileS-2 gene decreased from 28.1% (TP1) to 18.2% (TP2; p = 0.072) to 9.2% (TP3; p = 0.002). OCT MIC range remains stable at 0.5 to 1 mcg/ml across all three TPs. The proportion of isolates with reduced CHG susceptibility (MIC ≥ 4 mcg/ml) increased over the three TPs from 23.1 to 27.2% (p = 0.45) to 42.1% (p = 0.003). Active formulary regulations have an impact on the resistance profile of MRSA and can be used as a strategy to preserve the MRSA decolonization armamentarium.

Background: The effects of subinhibitory concentrations (sub-MICs) of antibacterial agents on the biofilm-forming ability of Staphylococcus aureus require further study., Aim: To investigate the effects of sub-MICs of chlorhexidine and mupirocin on biofilm formation in clinical meticillin-resistant Staphylococcus aureus (MRSA) isolates., Methods: MRSA isolates were collected from patients with bloodstream infections at a tertiary care hospital. The basal level of biofilm formation and biofilm induction by sub-MICs of chlorhexidine and mupirocin were evaluated by measuring biofilm mass stained with Crystal Violet., Findings: Of the 112 MRSA isolates tested, 63 (56.3%) and 44 (39.3%) belonged to sequence type (ST)5 and ST72 lineages, respectively, which are the predominant healthcare- and community-associated clones in South Korea. ST5 isolates were more likely to have chlorhexidine MIC ≥4 (73.0% vs 29.5%), resistance to mupirocin (23.8% vs 0%), agr dysfunction (73.0% vs 9.1%), and qacA/B gene (58.7% vs 2.3%) compared to ST72 isolates. The basal level of biofilm formation ability was frequently stronger in ST72 isolates compared to ST5 isolates (77.3% vs 12.7%). Sub-MICs of chlorhexidine and mupirocin promoted biofilm formation in 56.3% and 53.6%, respectively, of all isolates. Biofilm induction was more prevalent in ST5 isolates (85.7% for chlorhexidine, 69.8% for mupirocin) than in ST72 isolates (15.9% for chlorhexidine, 27.3% for mupirocin)., Conclusion: Sub-MICs of chlorhexidine and mupirocin promoted biofilm formation in half of the clinical MRSA isolates. Our results suggest that ST5 MRSA biofilm can be induced together with some other bacterial virulent factors following exposure to chlorhexidine, which might confer a survival advantage to this clone in the healthcare environment., (Copyright © 2020 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Aryl hydrocarbon receptor (AhR) antagonism can mitigate cellular damage associated with cerebral ischaemia and reperfusion (I/R) injury. This study investigated the neuroprotective effects of AhR antagonist administration before reperfusion in a rat stroke model and influence of the timing of AhR antagonist administration on its neuroprotective effects. Magnetic resonance imaging (MRI) was performed at baseline, immediately after, and 3, 8, and 24 h after ischaemia in the sham, control (I/R injury), TMF10 (trimethoxyflavone [TMF] administered 10 min post-ischaemia), and TMF50 (TMF administered 50 min post-ischaemia) groups. The TMF treatment groups had significantly fewer infarcts than the control group. At 24 h, the relative apparent diffusion coefficient values of the ischaemic core and peri-infarct region were significantly higher and relative T2 values were significantly lower in the TMF10 groups than in the control group. The TMF treatment groups showed significantly fewer terminal deoxynucleotidyl transferase dUTP nick-end labelling positive (+) cells (%) in the peri-infarct region than the control group. This study demonstrated that TMF treatment 10 or 50 min after ischaemia alleviated brain damage. Furthermore, the timing of AhR antagonist administration affected the inhibition of cellular or vasogenic oedema formation caused by a transient ischaemic stroke.

The purpose of this study was to investigate the high-level mupirocin resistance (HLMR) in Gram-positive bacteria isolated from companion animals. A total of 931 clinical specimens were collected from diseased pets. The detection of mupirocin-resistant bacteria and plasmid-mediated mupirocin resistance genes were evaluated by antimicrobial susceptibility tests, polymerase chain reactions, and sequencing analysis. Four-hundred and six (43.6%) bacteria were isolated and 17 (4.2%), including 14 staphylococci and 3 Corynebacterium were high-level mupirocin-resistant (MICs, ≥ 1,024 ug/mL) harboring mupA . Six staphylococci of HLMR strains had plasmid-mediated mupA -IS 257 flanking regions. The results show that HLMR bacteria could spread in veterinary medicine in the near future., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Korean Society of Veterinary Science.)

Background: Antimicrobial resistance is an increasingly serious problem in public health globally. Monitoring resistance levels within healthcare and community settings is critical to combat its ongoing increase. This study aimed to describe the rates and molecular mechanisms of mupirocin resistance in clinical Staphylococcus aureus isolates from Tygerberg Hospital, and to describe its association with strain types., Methods: We retrospectively selected 212 S. aureus isolates which were identified from blood samples and pus swabs during the years 2009-2011 and 2015-2017. The isolates were identified using conventional microbiological methods and genotyping was done using spa typing. Cefoxitin (30 μg) disc diffusion and the two disc strategy (5 μg and 200 μg) were used to determine susceptibility to methicillin and mupirocin, respectively. Isolates with high-level resistance were screened for the plasmid mediated genes mupA and mupB by PCR, and sequencing of the ileS gene was done for all isolates exhibiting low-level resistance to describe the mutations associated with this phenotype. Chi-square test was used to assess the associations between mupirocin resistance and S. aureus genotypes., Results: Of 212 S. aureus isolates, 12% (n = 25) were resistant to mupirocin, and 44% (n = 93) were methicillin resistant. Strain typing identified 73 spa types with spa t045 being the most predominant constituting 11% of the isolates. High-level mupirocin resistance was observed in 2% (n = 5), and low-level resistance in 9% (n = 20) of the isolates. The prevalence of high-level mupirocin resistance amongst MRSA and MSSA was 4 and 1% respectively, while the prevalence of low-level mupirocin resistance was significantly higher in MRSA (18%) compared to MSSA (3%), (p = 0.032). mupA was the only resistance determinant for high-level resistance, and the IleS mutation V588F was identified in 95% of the isolates which showed low-level resistance. A significant association was observed between spa type t032 and high-level mupirocin resistance, and types t037 and t012 and low-level resistance (p <  0.0001)., Conclusion: The study reported higher rates of low-level mupirocin resistance compared to high-level resistance, and in our setting, mupirocin resistance was driven by certain genotypes. Our study advocates for the continuous screening for mupirocin resistance in S. aureus in clinical settings to better guide treatment and prescribing practices.

A novel composite hydrogel was prepared as a dual drug delivery carrier. Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles were prepared to encapsulate simultaneously ketoprofen and mupirocin, as hydrophobic drug models. These microparticles were embedded in a physically crosslinked hydrogel of κ-carrageenan/locust bean gum. This composite hydrogel showed for both drugs a slower release than the obtained release from microparticles and hydrogel separately. The release of both drugs was observed during a period of 7 days at 37 °C. Different kinetic models were analyzed and the results indicated the best fitting to a Higuchi model suggesting that the release was mostly controlled by diffusion. Also, the drug loaded microparticles were spherical with average mean particle size of 1.0 μm, mesoporous, and distributed homogeneously in the hydrogel. The composite hydrogel showed a thermosensitive swelling behavior reaching 183% of swelling ratio at 37 °C. The composite hydrogel showed the elastic component to be higher than the viscous component, indicating characteristics of a strong hydrogel. The biocompatibility was evaluated with in vitro cytotoxicity assays and the results indicated that this composite hydrogel could be considered as a potential biomaterial for dual drug delivery, mainly for wound healing applications., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Staphylococcus aureus is one of the most common pathogens causing nosocomial and community-acquired infections associated with high morbidity and mortality. Mupirocin has been increasingly used for treatment of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) infections. The aim of this study was to determine the prevalence of mupirocin-resistant S. aureus (MuRSA), mupirocin-resistant MRSA (MuRMRSA), high-level MuRSA (HLMuRSA) and high-level MuRMRSA (HLMuRMRSA) worldwide., Methods: Online databases including Medline, Embase and Web of Science were searched (2000-2018) to identify studies addressing the prevalence of MuRSA, MuRMRSA, HLMuRSA and HLMuRMRSA. STATA v. software was used to interpret the data., Results: Of the 2243 records identified from the databases, 30 and 63 studies fulfilled the eligibility criteria for MuRSA and MuRMRSA, respectively. Finally, 27 and 60 studies were included separately for HLMuRSA and HLMuRMRSA, respectively. The analyses revealed pooled and averaged prevalences of MuRSA, MuRMRSA, HLMuRSA and HLMuRMRSA of 7.6% [95% confidence interval (CI) 6.2-9.0%], 13.8% (95% CI 12.0-15.6%), 8.5% (95% CI 6.3-10.7%) and 8.1% (95% CI 6.8-9.4%), respectively., Conclusion: Overall, these results show a global increase in the prevalence of HLMuRSA and HLMuRMRSA among clinical S. aureus isolates over time. However, there was only a significant increase in the prevalence of MuRMRSA compared with the other categories, especially MuRSA. Since mupirocin remains the most effective antibiotic for MSSA and MRSA decolonisation both in patients and healthcare personnel, a reduction of its effectiveness presents a risk for invasive infection. Monitoring of mupirocin resistance development remains critical., (Copyright © 2019 International Society for Antimicrobial Chemotherapy. Published by Elsevier Ltd. All rights reserved.)

Previous studies have shown that the administration of antibiotics at subinhibitory concentrations stimulates biofilm formation by the majority of multidrug-resistant Staphylococcus aureus (MRSA) strains. Here, we investigated the effect of subinhibitory concentrations of mupirocin on biofilm formation by the community-associated (CA) mupirocin-sensitive MRSA strain USA300 and the highly mupirocin-resistant clinical S. aureus SA01 to SA05 isolates. We found that mupirocin increased the ability of MRSA cells to attach to surfaces and form biofilms. Confocal laser scanning microscopy (CLSM) demonstrated that mupirocin treatment promoted thicker biofilm formation, which also correlated with the production of extracellular DNA (eDNA). Furthermore, quantitative real-time PCR (RT-qPCR) results revealed that this effect was largely due to the involvement of holin-like and antiholin-like proteins (encoded by the cidA gene), which are responsible for modulating cell death and lysis during biofilm development. We found that cidA expression levels significantly increased by 6.05- to 35.52-fold ( P  < 0.01) after mupirocin administration. We generated a cidA -deficient mutant of the USA300 S. aureus strain. Exposure of the ΔcidA mutant to mupirocin did not result in thicker biofilm formation than that in the parent strain. We therefore hypothesize that the mupirocin-induced stimulation of S. aureus biofilm formation may involve the upregulation of cidA ., (Copyright © 2020 American Society for Microbiology.)

Methicillin-resistant Staphylococcus aureus (MRSA) opportunistic infections are a major health burden. Decolonization of hospitalized patients with mupirocin (MUP) has reduced the incidence of infection but has led to MUP resistance. DIBI is a developmental-stage anti-infective agent that sequesters bacterial iron and bolsters innate host iron-withdrawal defenses. Clinical isolates possessing low, high, or no MUP resistance all had similarly high susceptibilities to DIBI. Intranasal DIBI reduced nares bacterial burdens in mice to the same extent as MUP. No resistance was found after exposure to DIBI., (Copyright © 2020 American Society for Microbiology.)

Staphylococcus aureus is a major cause of severe invasive infections. The increasing incidence of infections caused by antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA), calls for exploration of new approaches to treat these infections. Mupirocin is an antibiotic with a unique mode of action that is active against MRSA, but its clinical use is restricted to topical administration because of its limited plasma stability and rapid degradation to inactive metabolites. Mupirocin was identified by a machine learning approach to be suitable for nano-liposome encapsulation. The computational predictions were verified experimentally and PEGylated nano-liposomal formulation of mupirocin (Nano-mupirocin) was developed. The aim of this study was to investigate the efficacy of this formulation when administered parenterally for the treatment of S. aureus invasive infections. Nano-mupirocin exhibited prolonged half-life of active antibiotic and displayed superior antimicrobial activity against S. aureus than free mupirocin in the presence of plasma. Parenteral application of Nano-mupirocin in a murine model of S. aureus bloodstream infection resulted in improved antibiotic distribution to infected organs and in a superior therapeutic efficacy than the free drug. Parenterally administered Nano-mupirocin was also more active against MRSA than free mupirocin in a neutropenic murine lung infection model. In addition, Nano-mupirocin was very efficiently taken up by S. aureus-infected macrophages via phagocytosis leading to enhanced delivery of mupirocin in the intracellular niche and to a more efficient elimination of intracellular staphylococci. The outcome of this study highlights the potential of Nano-mupirocin for the treatment of invasive MRSA infections and support the further clinical development of this effective therapeutic approach., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: The aim of this study was to evaluate the effect of subinhibitory concentrations of trans -anethole on antibacterial and antibiofilm properties of mupirocin against mupirocin-resistant Staphylococcus aureus strains. Methods: Following parameters were examined: isolates susceptibility to antibiotics, minimum inhibitory concentration (MIC) of trans -anethole, antibacterial activity of mupirocin/ trans -anethole combination, detection of ileS2 gene, genotypic relativity of isolates using pulsed-field gel electrophoresis method, and the influence of mupirocin/ trans -anethole combination on S. aureus biofilm formation. Results: Our study revealed that trans -anethole combined with mupirocin increased the growth inhibition zone diameter around the mupirocin disk, independently on S. aureus strains susceptibility to this antibiotic. Moreover, combination of subinhibitory (MIC 50 ) concentration of mupirocin and trans -anethole significantly decreased biofilm biomass. Conclusions: Anethole appeared efficient in increasing susceptibility to mupirocin and decreasing biofilm formation in trans- Anethole appeared efficient in increasing susceptibility to mupirocin and decreasing biofilm formation in S. aureus strains used in this study. Reduction of biofilm formation can potentially protect against S. aureus anethole in combination with mupirocin can increase the mupirocin activity against methicillin-resistant and mupirocin-resistant trans- anethole in combination with mupirocin can increase the mupirocin activity against methicillin-resistant and mupirocin-resistant S. aureus strains.

Background: The widespread of methicillin-resistant Staphylococcus aureus (MRSA) antimicrobial decolonization in the clinical setting may lead to an increase in the prevalence of multiresistance to coagulase-negative staphylococci (CoNS) owing to their selection. This study aimed to investigate the impact of MRSA decolonization strategies, using mupirocin and chlorhexidine, on their CoNS susceptibility., Methods: A total of 312 CoNS isolates were collected before starting the decolonization protocols "baseline strains" (BLS) group, 330 isolates were collected after application of the targeted decolonization protocol "targeted decolonization strains" group, and 355 isolates were collected after application of the universal decolonization protocol "universal decolonization strains" group. Methicillin-resistant CoNS (MR-CoNS) were identified and tested for mupirocin and chlorhexidine susceptibilities. Heptaplex polymerase chain reaction assay was applied for simultaneous screening for chlorhexidine (CHX-R) and mupirocin resistance (Mu-R) genes., Results: Mu-R prevalence of MR-CoNS among the BLS group was considered moderate (9.1%); however, CHX-R in the BLS group was 5.8%, the rate of which significantly increased among the universal decolonization strains group., Discussion: Both MRSA decolonization strategies have an additional benefit in reducing the prevalence of MR-CoNS. The prevalence Mu-R rate didn't change significantly during either of the MRSA decolonization practices that may be due to the local nature of mupirocin application on the nasal mucosa only. In contrast CHX-R that was found to be significantly higher among the UDS group., Conclusions: Our findings indicate that both MRSA decolonization strategies have an additional benefit in reducing the prevalence of MR-CoNS. Although the universal MRSA decolonization has superior efficacy in decolonization of CoNS, it may increase the risk of selecting CHX-R and Mu-R. In addition, other potential resistance genes should be studied., (Copyright © 2019 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Resistance to methicillin and mupirocin in coagulase-negative staphylococci (CoNS) is considered as one of the most important issues. Meanwhile, use of phenotypic methods in detecting the resistance to methicillin and mupirocin has a lower accuracy and speed compared to other molecular methods, such as High-Resolution Melting Analysis (HRM). In this study, HRM technique was used to identify CoNS resistance stains., Methods: This experimental study was done on 86 isolates of CoNS strains isolated at Hamadan Hospital. Pheno-typic tests were used to identify Staphylococcus saprophyticus and S. epidermidis. Methicillin and Mupirocin resistant strains were tested using the MIC and HRM methods, and sensitivity and specificity of the primers were determined based on melting curve temperature range. In addition, data was analyzed by Applied Biosystems StepOne v 2.3 and Applied Biosystems HRM v 3.0.1 software., Results: Eighty-six (86) coagulase-negative isolates were isolated from different clinical specimens. Among these, 69 isolates of S. epidermidis and 17 isolates of S. saprophyticus were identified. Of the 69 S. epidermidis isolates, 19 isolates with oxacillin MIC ≥ 0.5 µg/mL and methicillin-resistant, and 11 isolates with mupirocin MIC ≥ 32 µg/mL and resistant to mupirocin. Of the 17 S. saprophyticus isolates, three isolates with oxacillin MIC ≥ 0.5 µg/mL were also methicillin-resistant, and one isolate with mupirocin MIC ≥ 32 µg/mL was resistant to mupirocin. Melting curve analysis for mecA and mupA primers was determined 81.7 ± 0.5°C and 74 ± 0.5°C, respectively. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of HRM assay for detection of methicillin and mupirocin strains testing were 100%., Conclusions: Identification of methicillin and mupirocin resistance in CoNSs using the HRM method has high sensitivity and specificity. Molecular methods are more accurate and faster than phenotypic methods and can identify a large number of resistant isolates in a short time.

After the introduction of cocaine to the medical practice, local anaesthetics (LA) became essential in pain control. LA infiltration along the incision may be used to provide surgical anaesthesia or postoperative analgesia. This study aimed to compare the antimicrobial effects of the topical antimicrobial agent mupirocine with those of the LA lidocaine and the combination of lidocaine and adrenalin. In our study, the in vitro antimicrobial effects of 1 mL sterile saline, 20 mg/mL mupirocine, 20 mg/mL Lidocaine, and 20 mg/mL Lidocaine and Adrenaline were tested against Staphylococcus aureus American type culture collection (ATCC) 29213, Pseudomonas aeruginosa ATCC 27853, and Escherichia coli ATCC 25922 as Group C (Control), Group M (Mupirocine), Group L (Lidocaine), and Group LA (Lidocaine + adrenaline), respectively. S aureus ATCC 29213, P aeruginosa ATCC 27853, and E coli ATCC 25922 were cultured onto Mueller-Hinton agar (Oxoid, UK) plates for 18 to 24 hours at 37°C. Colonies from these plates were suspended in sterile saline and a 0.5 McFarland turbidity standard suspension (corresponding to 1.5 × 10 8  CFU/mL) of each isolate was prepared. S Aureus ATCC 29213 inhibition zone diameter values of Group M, Group LA, and Group L were significantly higher compared with the group C (P ˂ 0.05). P aeruginosa ATCC 27853 inhibition zone diameter values of Group M and Group LA were significantly higher compared with the group C (P ˂ 0.05). E coli ATCC 25922 inhibition zone diameter values of Group M, Group LA, and Group L were significantly higher compared to the group C (P ˂ 0.05). LA infiltration along the incision may be used to provide surgical anaesthesia or postoperative analgesia. Considering that LAs show antimicrobial effects besides their analgesic effects, they may contribute to preventing the development and reducing the rate of surgical infections, decreasing the requirement to administer antibiotics. However, caution should be exercised not to antagonise the effective treatment of surgical infections, remembering that controversy on the antimicrobial effects of LAs remains in the literature. Therefore, further comprehensive studies with larger patient populations are warranted to demonstrate the antimicrobial effects of LAs., (© 2019 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: Mupirocin is one of the few antimicrobials active against methicillin-resistant Staphylococcus aureus (MRSA), and is frequently used for the eradication of MRSA nasal colonisation in humans. Initially, mupirocin resistance was recognised in human S. aureus, including MRSA isolates, then also among coagulase-negative staphylococci (CoNS). Nowadays, mupirocin resistance is occasionally observed in canine staphylococci, along with Staphylococcus pseudintermedius (MRSP) strains, as well as CoNS, which usually show methicillin resistance. In the current study, high-level mupirocin resistance in methicillin-resistant staphylococci isolated from diseased dogs and cats was investigated., Results: Among 140 methicillin-resistant staphylococci isolates from dogs and cats, three showed high-level mupirocin resistance in a screening test using the agar disk diffusion method. One was recognised as methicillin-resistant S. aureus, one as methicillin-resistant S. pseudintermedius, and one as methicillin-resistant Staphylococcus haemolyticus. S. pseudintermedius and S. aureus were isolated from dogs, S. haemolyticus was obtained from a cat. All isolates showed high-level mupirocin resistance, confirmed by minimum inhibitory concentration (MIC) values of above 1024 μg/ml and the presence of the plasmid-located gene ileS2. This is the first report on the detection of high-level mupirocin resistance (HLMR) in S. haemolyticus of feline origin., Conclusions: This study revealed the occurrence of HLMR in three Staphylococcus isolates obtained from companion animals in Poland. The results of this study indicate that the monitoring of mupirocin resistance in staphylococci of animal origin, especially in methicillin-resistant isolates, is strongly recommended.

Mupirocin is an antibiotic from monocarboxylic acid class used as antibacterial agent against methicillin-resistant Staphylococcus aureus (MRSA) and can be obtained as a mixture of four pseudomonic acids by Pseudomonas fluorescens biosynthesis. Nowadays improving antibiotics occupies an important place in the pharmaceutical industry as more and more resistant microorganisms are developing. Mupirocin is used to control the MRSA outbreaks, for infections of soft tissue or skin and for nasal decolonization. Due to its wide use without prescription, the microorganism's resistance to Mupirocin increased from up to 81%, thus becoming imperative its control or improvement. As the biotechnological production of Mupirocin has not been previously reviewed, in the present paper we summarize some consideration on the biochemical process for the production of pseudomonic acids (submerged fermentation and product recovery). Different strains of Pseudomonas, different culture medium and different conditions for the fermentation were analysed related to the antibiotics yield and the product recovery step is analysed in relation to the final purity. However, many challenges have to be overcome in order to obtain pseudomonic acid new versions with better properties related to antibacterial activity.

Few studies describe the molecular characterization of mupirocin resistance in Staphylococcus aureus strains. In this study, we evaluated the characteristics of mupirocin resistance in S. aureus isolates for 1-year period in Tehran, Iran. In a cross-sectional study, we collected 51 unique mupirocin-resistant strains obtained from 648 S. aureus isolates. High- and low-level resistance were determined by minimum inhibitory concentration with broth microdilution method. Presence of the genes for resistance to antibiotics and toxins was detected by polymerase chain reaction assays. Genotyping was performed by S. aureus protein A ( spa ) and staphylococcal cassette chromosome mec (SCC mec ) typing, whereas clones were determined by multilocus sequence typing. Among mupirocin-resistant isolates, methicillin-resistant S. aureus (MRSA) 23 (45.1%) and 28 (54.9%) isolates were classified as high- and low-level mupirocin resistance, respectively. Among the 51 tested strains 25 (49%) isolates were positive for mupA genes. Seven different clones were detected in this study. High-level mupirocin-resistant (HLMUPR) strains belonged to ST8-SCC mec IV/t064 ( n  = 10, 19.6%), ST5-SCC mec IV/t002 ( n  = 5, 9.8%), ST8-SCC mec IV/t008 ( n  = 4, 7.8%), and ST239-SCC mec III/t631 ( n  = 4, 7.8%) clones, while low-level mupirocin-resistant (LLMUPR) strains belonged to ST22-SCC mec IV/t790 ( n  = 11, 21.6%), ST239-SCC mec III/t860 ( n  = 9, 17.7%), and ST15-SCC mec IV/t084 ( n  = 8, 15.7%) clones. Two strains belonged to ST22-SCC mec IV/t790 clone, despite carrying mupA gene, and demonstrated LLMUPR phenotype. One ST8-SCC mec IV/t008 strain with HLMUPR was confirmed as Vancomycin-intermediate S. aureus strain. Our data demonstrated the need for thorough epidemiological monitoring and a routine mupirocin testing program to prevent and detect mupirocin resistance in MRSA.

Aim: To determine the computer-predicted anticancer activity of mupirocin and to compare its activities with those determined for another polyene antibiotic, batumin. Materials & methods: Molecular docking, cytotoxicity assays, cell microscopy and cell cycle progression were studied in cancer and nontumorigenic cell lines. Results & conclusion: Cytotoxicity of mupirocin against several cancerous cell lines was detected with the highest one (IC 50  = 5.4 μg/ml) against melanoma cell line. The profile of cytotoxicity of mupirocin was similar to that reported for batumin. Nevertheless, the morphology of cells treated with these antibiotics and alterations in cell cycle progression suggested possible dissimilarity in their mechanisms of action. Selective cytotoxicity of mupirocin against melanoma cells potentiates further studies to discover nontoxic drugs for melanoma prevention.

Introduction: The adoption of the International Society for Peritoneal Dialysis guideline of using mupirocin ointment has been limited by fear of developing mupirocin-resistant organisms. We performed a surveillance program of a large peritoneal dialysis (PD) unit., Methods: We performed 1,175 surveillance swabs from anterior nares, PD catheter exit site, groin, and axilla, from 240 patients. The mean interval between swabs was 3.3 months., Results: Colonization by Staphylococcus aureus ( S. aureus ) or Pseudomonas species was 9.5% and 10.9%, respectively. Despite adopting a universal policy of applying mupirocin to PD catheter exit sites in 2001, no instances of mupirocin-resistant S. aureus were identified. Moreover, patients who grew S. aureus from surveillance swabs did not experience higher peritonitis rates than those with "no growth." This was in contrast to patients who grew Pseudomonas or enteric organisms. There were no differences in patient demographics for those who grew S. aureus , Pseudomonas , or enteric organisms (compared with "no-growth" patients)., Conclusion: Our results suggest that the application of mupirocin ointment appeared to minimize peritonitis of patients colonized with S. aureus . The use of mupirocin in this patient cohort has not led to mupirocin resistance. The increased peritonitis rate of patients who grew Pseudomonas or enteric organisms is of interest. We propose that greater attention to hygiene and catheter care in these patients is warranted. The increasing use of paid healthcare workers attending patients daily to help perform PD (assisted PD) gives an opportunity for us to address these wider issues., (Copyright © 2019 International Society for Peritoneal Dialysis.)

In Latin America, few studies have been done in mupirocin resistance and biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA). This study investigated mupirocin-resistance in MRSA isolates from pediatric patients with bacteremia and their ability to form biofilm. Antibiotic resistance was analyzed with the Kirby-Bauer test and the broth microdilution method. Bacterial biofilm formation was measured using the crystal violet assay. Among MRSA isolates, 2.3 % (5/217) exhibited a high level of mupirocin-resistance with a minimum inhibitory concentration of >512 μg/mL, in addition to cross-resistance with clindamycin, erythromycin, gentamicin, and ciprofloxacin. Remarkably, biofilm formation in such isolates was moderate to high. This is the first report published in Argentina on clinical isolates of mupirocin-resistant MRSA and it is critical for following its evolution over time at a local level and in the Latin American region., (Sociedad Argentina de Pediatría.)

Between September 2013 and March 2016, 26 (1.95 %) of 1333 Staphylococcus aureus clinical isolates from a Chinese hospital were found to be resistant to mupirocin, including 18 (1.35 %) with high-level mupirocin resistance and 8 (0.6 %) with low-level mupirocin resistance. Among the 18 isolates with high-level mupirocin resistance, 17 were associated with plasmid-mediated mupA. Meanwhile, the 8 isolates with low-level mupirocin resistance were shown to have a V588F mutation in ileS. A total of 14 sequence types (STs) and 18 spa types were identified. All four isolates with t062 belonged to ST965. Three ST5-MRSA-SCCmec II were linked to t311, which was not previously reported. Furthermore, ST764-MRSA-SCCmec II-t002, exclusively found in Japan before, was identified in this study. In conclusion, we observed relatively low prevalence of mupirocin resistance among S. aureus with considerable heterogeneity in East China. Newly emerging MRSA clones with high-level mupirocin resistance should be of concern.

Introduction: The evolution of antibiotics in the last century has revolutionized the field of medicine and led this field to higher level of success in treating mild to severe infections, but the inappropriate use of these life saving drugs has been accompanied with the appearance of resistant strains to these agents., Aims & Objectives: The aim of the study was to determine the prevalence rate of high and low-level mupirocin resistance in methicillin resistant staphylococcus,and to find out resistance to other antibiotics., Materials & Methods: This study was conducted on 100 Staphylococcus isolates recovered from pus samples. Conventional disc diffusion tests were used for the detection of high and low level mupirocin resistance (mupirocin 5µg and 200µg discs) and for various other antimicrobials for example cephalexin, erythromycin, doxycycline, oxacillin, linezolid etc. Results: Outof 100 Staphylococcus isolates processed during the study period in the department of microbiology, 74 were Staphylococcus aureus (S.aureus) and 26 were Coagulase negative Staphylococcus (CoNS). Among S.aureus 43.4% were Methicillin resistant Staphylococcus aureus (MRSA) and 56.6% were Methicillin sensitive Staphylococcus aureus (MSSA), whereas among CoNS 42% were methicillin resistant and 58% were methicillin sensitive. We observed 6.75% of high level mupirocin resistance among Staphylococcus aureus and 19.23% among Coagulase negative staphylococcus., Conclusion: It was concluded that an inappropriate excessive use of mupirocin leads to a rapid increase in high-level resistance to mupirocin and other antibiotics in CoNS, affecting the treatment lines and success rate of infection control in hospital settings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Nasal carriage of Staphylococcus aureus is very common among health care workers, and treatment with mupirocin is one of the choicest antibiotics available. But with the rampant usage of mupirocin like other antibiotics, the emergence of mupirocin resistance is also on rise. This resistance is both low level as well as high level among the isolated strains., Aim: To screen for the high-level mupirocin resistance among the isolated Staphylococcus strains by Kirby Bauer disk diffusion method., Materials and Methods: A total of 200 clinical isolates were tested for high level mupirocin resistance by disk diffusion method using Himedia disks., Results: Among the 200 nasal swabs, 26 (13%) showed growth of S. aureus, whereas 174 (87%) showed the growth of coagulase negative staphylococcus (CONS) spp. Mupirocin resistance was observed only among CONS spp, which was 15% for low-level mupirocin and 8% for high-level mupirocin resistance. No mupirocin resistance was observed among the Staphylococcus spp., Conclusion: The identification of Mupirocin resistance will guide us to utilize the antibiotic in a judicious way to treat the nasal carriage effectively., (© 2019 S. Karger AG, Basel.)