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1.
Virulence ; 15(1): 2399798, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39229975

ABSTRACT

Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant S. aureus (MRSA) strains being a major contributor in both community and hospital settings. S. aureus relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both in vitro and in vivo. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the ΔyjbIH mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the ΔyjbH mutant. This work continues to define the importance of YjbH in the pathogenesis of S. aureus infection as well as identify a new pathway important for Hla production.


Subject(s)
Bacterial Proteins , Bacterial Toxins , Gene Expression Regulation, Bacterial , Hemolysin Proteins , Staphylococcus aureus , Trans-Activators , Hemolysin Proteins/metabolism , Hemolysin Proteins/genetics , Bacterial Toxins/metabolism , Bacterial Toxins/immunology , Bacterial Toxins/genetics , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Staphylococcus aureus/pathogenicity , Staphylococcus aureus/immunology , Staphylococcus aureus/genetics , Mice , Animals , Trans-Activators/genetics , Trans-Activators/metabolism , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/immunology , Staphylococcal Skin Infections/pathology , Methicillin-Resistant Staphylococcus aureus/pathogenicity , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/immunology , Skin/microbiology , Skin/pathology , Skin/immunology , Virulence Factors/genetics , Humans , Soft Tissue Infections/microbiology , Soft Tissue Infections/immunology , Staphylococcal Infections/immunology , Staphylococcal Infections/microbiology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cytokines/metabolism , Cytokines/immunology , Cytokines/genetics
2.
Int J Mol Sci ; 25(17)2024 Aug 23.
Article in English | MEDLINE | ID: mdl-39273114

ABSTRACT

Staphylococcus aureus acts both as a colonizing commensal bacterium and invasive pathogen. Nasal colonization is associated with an increased risk of infection caused by the identical strain. In patients with atopic dermatitis (AD), the degree of S. aureus colonization is associated with the severity of the disease. Here, we comparatively analyzed the in vivo transcriptional profile of S. aureus colonizing the nose and non-diseased skin (non-lesional skin) as opposed to the diseased skin (lesional skin-defined here as infection) of 12 patients with AD. The transcriptional profile during the asymptomatic colonization of the nose closely resembled that of the lesional skin samples for many of the genes studied, with an elevated expression of the genes encoding adhesion-related proteins and proteases. In addition, the genes that modify and remodel the cell wall and encode proteins that facilitate immune evasion showed increased transcriptional activity. Notably, in a subgroup of patients, the global virulence regulator Agr (accessory gene regulator) and downstream target genes were inactive during nasal colonization but upregulated in the lesional and non-lesional skin samples. Taken together, our results demonstrate a colonization-like transcriptional profile on diseased skin and suggest a role for the peptide quorum sensing system Agr during the transition from asymptomatic nasal colonization to skin colonization/infection.


Subject(s)
Dermatitis, Atopic , Gene Expression Profiling , Gene Expression Regulation, Bacterial , Skin , Staphylococcal Infections , Staphylococcus aureus , Dermatitis, Atopic/microbiology , Dermatitis, Atopic/genetics , Humans , Staphylococcus aureus/genetics , Skin/microbiology , Skin/metabolism , Staphylococcal Infections/microbiology , Staphylococcal Infections/genetics , Female , Male , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Adult , Transcriptome , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/genetics , Nasal Mucosa/microbiology , Trans-Activators
3.
BMJ Case Rep ; 17(8)2024 Aug 16.
Article in English | MEDLINE | ID: mdl-39153758

ABSTRACT

Three family members attended their general practice and emergency department over a 3-month period with recurrent skin and soft tissue infections (SSTIs) such as paronychia, submandibular carbuncle and groin and gluteal abscess requiring surgical drainage. Only when two family members were concurrently admitted with abscesses requiring drainage under general anaesthetic was the definitive diagnosis reached. The wound swabs identified methicillin-resistant Staphylococcus aureus (MRSA) and subsequent identification of the exotoxin Panton-Valentine leukocidin (PVL). Following MRSA decolonisation therapy with mupirocin and octenidine, only one family member has had one recurrence of an SSTI with MRSA isolated from the wound. When patients present with a history of recurrent SSTIs or a family all have had similar presentations, the clinician should consider MRSA with PVL exotoxin infection. Then patients must be referred for confirmation to ensure management is effective for the SSTI and prescribe MRSA decolonisation therapy concurrently to reduce recurrence.


Subject(s)
Bacterial Toxins , Exotoxins , Leukocidins , Methicillin-Resistant Staphylococcus aureus , Recurrence , Soft Tissue Infections , Humans , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Methicillin-Resistant Staphylococcus aureus/drug effects , Soft Tissue Infections/microbiology , Soft Tissue Infections/therapy , Soft Tissue Infections/drug therapy , Male , Female , Staphylococcal Skin Infections/drug therapy , Staphylococcal Skin Infections/microbiology , Anti-Bacterial Agents/therapeutic use , Adult , Staphylococcal Infections/drug therapy , Staphylococcal Infections/diagnosis , Staphylococcal Infections/microbiology , Middle Aged , Mupirocin/therapeutic use
4.
Nanoscale ; 16(35): 16329-16343, 2024 Sep 12.
Article in English | MEDLINE | ID: mdl-39129708

ABSTRACT

Ultrasonic nanotechnology represents a groundbreaking advancement in the management of Staphylococcus aureus skin infections, addressing the significant limitations of conventional treatments. S. aureus poses substantial challenges, including antibiotic resistance and biofilm formation, necessitating novel and effective approaches. By harnessing the power of ultrasonic waves and nanostructures, this technology offers a precise mechanism to disrupt bacterial cells, enhancing antibiotic susceptibility and facilitating the eradication of bacterial colonies. This innovative approach not only improves treatment outcomes, but also offers a non-invasive and highly efficient alternative to traditional methods. Recent studies have demonstrated the remarkable efficacy of ultrasonic nanotechnology, showcasing its ability to revolutionize the treatment paradigm for S. aureus infections. Ongoing research is dedicated to refining treatment protocols, developing new nanostructures, and assessing clinical applicability, with a focus on overcoming challenges such as scalability and long-term effectiveness. This review provides a comprehensive overview of the current state of ultrasonic nanotechnology in combating S. aureus skin infections, detailing its mechanism of action, summarizing key research findings, and highlighting its superiority over conventional modalities. Accumulating evidence underscores its potential as a pivotal development in modern science and technology, promising significant advancements in infection management strategies. As research continues to evolve, the optimization of protocols, exploration of innovative applications, and translation into clinical practice are poised to further solidify the transformative impact of ultrasonic nanotechnology in the medical field.


Subject(s)
Nanotechnology , Staphylococcal Skin Infections , Staphylococcus aureus , Staphylococcus aureus/drug effects , Humans , Staphylococcal Skin Infections/drug therapy , Staphylococcal Skin Infections/therapy , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Biofilms/drug effects , Nanostructures/chemistry , Nanostructures/therapeutic use , Ultrasonic Therapy
5.
Sci Rep ; 14(1): 19326, 2024 08 20.
Article in English | MEDLINE | ID: mdl-39164371

ABSTRACT

The whole genome sequence (WGS) of prevalent MRSA strains harboring mecA gene obtained from skin and soft tissue infections (SSTIs) in Nigerian hospitals were profiled for pathogenomic structure and evaluated for clonal diversity. The two MRSA strains identified among 66 isolated multi-drug resistant S. aureus from a collection of 256 clinical samples were phenotyped for antibiotic resistance and genotyped for mecA, SCCmec, and spa types. The mecA positive MRSA was analysed using whole-genome sequencing for resistomes, virulomes, phylogenomic profiles and clonal diversity. The identified MRSA-CC7-ST789-t091-SCCmecV strains from a female child (aged 1 year) with severe otorrhea and an adult male (aged 23) with purulent wound abscess showed high-level resistance to streptomycin, vancomycin, kanamycin, sulfamethoxazole and ciprofloxacin. Both strains harbored abundant resistomes, inherent plasmids, chromosomal replicons and typical seven housekeeping genes (arc3, aroE4, glpF1, gmk4, pta4, tpi6, yqiL3). The most abundant putative virulomes were pathogenesis-associated proteins (included hemolysin gamma, leucocidins, proteases, staphylococcal superantigen/enterotoxin-like genes (Set/Ssl), capsule- and biofilm-associated genes, and hyaluronate lyase). Comparative phylogenomic analysis revealed the relatedness of the two clonal strains with prevalent MRSA-CC7 pathotypes observed in Italy (2013 and 2014), Denmark (2014), Thailand (2015 and 2016), USA (2018), and Nigeria (2016 and 2020); and share high genetic similarities with livestock strains from cow milk and cattle. Identified MRSA-CC7-ST789-t091-SCCmecV pathotypes implicated in SSTIs from Nigeria harboring repertoires of antibiotic resistance and virulence genes, and genetic relatedness with livestock strains; show the possibility of gene transfer between animal and human. Adequate hospital MRSA infection control and geno-epidemiological surveillance for animal and human transfer is required.


Subject(s)
Methicillin-Resistant Staphylococcus aureus , Phylogeny , Soft Tissue Infections , Humans , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Animals , Soft Tissue Infections/microbiology , Soft Tissue Infections/epidemiology , Female , Male , Whole Genome Sequencing , Infant , Young Adult , Anti-Bacterial Agents/pharmacology , Nigeria , Staphylococcal Infections/microbiology , Staphylococcal Infections/epidemiology , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/epidemiology , Microbial Sensitivity Tests , Drug Resistance, Multiple, Bacterial/genetics
6.
PLoS Pathog ; 20(8): e1012056, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39208402

ABSTRACT

The Staphylococcus sp. are a dominant part of the human skin microbiome and present across the body. Staphylococcus epidermidis is a ubiquitous skin commensal, while S. aureus is thought to colonize at least 30% of the population. S. aureus are not only colonizers but a leading cause of skin and soft tissue infections and a critical healthcare concern. To understand how healthy human skin may differentiate commensal bacteria, such as S. epidermidis, from the potential pathogen methicillin-resistant S. aureus (MRSA), we use ex vivo human skin models that allow us to study this host-bacterial interaction in the most clinically relevant environment. Our work highlights the role of the outer stratum corneum as a protective physical barrier against invasion by colonizing Staphylococci. We show how the structural cells of the skin can internalize and respond to different Staphylococci with increasing sensitivity. In intact human skin, a discriminatory IL-1ß response was identified, while disruption of the protective stratum corneum triggered an increased and more diverse immune response. We identified and localized tissue resident Langerhans cells (LCs) as a potential source of IL-1ß and go on to show a dose-dependent response of MUTZ-LCs to S. aureus but not S. epidermidis. This suggests an important role of LCs in sensing and discriminating between bacteria in healthy human skin, particularly in intact skin and provides a detailed snapshot of how human skin differentiates between friend and potential foe. With the rise in antibiotic resistance, understanding the innate immune response of healthy skin may help us find ways to enhance or manipulate these natural defenses to prevent invasive infection.


Subject(s)
Interleukin-1beta , Skin , Staphylococcus aureus , Staphylococcus epidermidis , Humans , Interleukin-1beta/metabolism , Skin/microbiology , Skin/immunology , Staphylococcus aureus/immunology , Staphylococcal Infections/microbiology , Staphylococcal Infections/immunology , Staphylococcal Infections/metabolism , Langerhans Cells/immunology , Langerhans Cells/microbiology , Methicillin-Resistant Staphylococcus aureus/immunology , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/immunology , Microbiota/immunology
7.
Cell Rep ; 43(7): 114486, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-38990718

ABSTRACT

Skin/soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) pose a major healthcare burden. Distinct inflammatory and resolution phases comprise the host immune response to SSTIs. Resolution is a myeloid PPARγ-dependent anti-inflammatory phase that is essential for the clearance of MRSA. However, the signals activating PPARγ to induce resolution remain unknown. Here, we demonstrate that myeloid glucose transporter 1 (GLUT-1) is essential for the onset of resolution. MRSA-challenged macrophages are unsuccessful in generating an oxidative burst or immune radicals in the absence of GLUT-1 due to a reduction in the cellular NADPH pool. This translates in vivo as a significant reduction in lipid peroxidation products required for the activation of PPARγ in MRSA-infected mice lacking myeloid GLUT-1. Chemical induction of PPARγ during infection circumvents this GLUT-1 requirement and improves resolution. Thus, GLUT-1-dependent oxidative burst is essential for the activation of PPARγ and subsequent resolution of SSTIs.


Subject(s)
Glucose Transporter Type 1 , Methicillin-Resistant Staphylococcus aureus , Soft Tissue Infections , Animals , Glucose Transporter Type 1/metabolism , Glucose Transporter Type 1/genetics , Mice , Soft Tissue Infections/microbiology , Soft Tissue Infections/metabolism , Soft Tissue Infections/pathology , PPAR gamma/metabolism , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/metabolism , Staphylococcal Skin Infections/pathology , Staphylococcal Skin Infections/drug therapy , Mice, Inbred C57BL , Macrophages/metabolism , Macrophages/microbiology , Staphylococcal Infections/metabolism , Staphylococcal Infections/microbiology
8.
Emerg Infect Dis ; 30(8): 1724-1726, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39043433

ABSTRACT

Continued detection of Panton-Valentine leukocidin-positive Staphylococcus aureus in samples from a family with severe repeated skin infections and their pet cat suggests transmission between the family and the cat. Decolonizing the pet led to successful elimination of the bacteria from the household. Clinicians should consider pet cats as possible reinfection sources.


Subject(s)
Bacterial Toxins , Exotoxins , Leukocidins , Pets , Staphylococcal Infections , Staphylococcus aureus , Leukocidins/genetics , Exotoxins/genetics , Cats , Bacterial Toxins/genetics , Animals , Staphylococcus aureus/genetics , Staphylococcus aureus/isolation & purification , Pets/microbiology , Humans , Staphylococcal Infections/microbiology , Staphylococcal Infections/veterinary , Male , Cat Diseases/microbiology , Cat Diseases/diagnosis , Female , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/veterinary , Family , Adult
9.
Antimicrob Agents Chemother ; 68(9): e0128123, 2024 Sep 04.
Article in English | MEDLINE | ID: mdl-39082883

ABSTRACT

Pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy were evaluated using data from omadacycline-treated patients with acute bacterial skin and skin structure infections (ABSSSI) enrolled in two phase 3 studies. Patients received omadacycline 100 mg intravenously (IV) every 12 hours for two doses, followed by 100 mg IV every 24 hours (q24h), with the option to switch to 300 mg oral (PO) q24h after 3 days or 450 mg PO q24h for two doses, followed by 300 mg PO q24h for a total duration of 7-14 days. Clinical response was evaluated at 48-72 hours [early clinical response (ECR)], end of treatment (EOT), and 7-14 days after EOT. Using a population pharmacokinetic (PK) model and PK data from patients with Staphylococcus aureus at baseline, omadacycline free-drug plasma area under the concentration-time curve (AUC) values were determined, and the relationships between free-drug plasma AUC:MIC ratio and dichotomous efficacy endpoints were evaluated. Using these relationships, the population PK model, simulation, and an omadacycline MIC distribution for S. aureus, mean percent probabilities of response were evaluated. Statistically significant PK--PD relationships were identified for ECR (P = 0.016 and 0.013 for optimized two- and three-group free-drug plasma AUC:MIC ratios, respectively). At an MIC value of 0.5 µg/mL, percent probabilities of model-predicted success for ECR based on the univariable PK-PD relationships using continuous and two-group free-drug plasma AUC:MIC ratio variables were 91.9 and 95.6%, respectively, for the IV-to-PO dosing regimen and 89.3 and 88.4%, respectively, for the PO-only dosing regimen. These data support for omadacycline IV-to-PO and PO-only dosing regimens for ABSSSI and an omadacycline susceptibility breakpoint of 0.5 µg/mL for S. aureus.


Subject(s)
Anti-Bacterial Agents , Microbial Sensitivity Tests , Tetracyclines , Humans , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Tetracyclines/pharmacokinetics , Tetracyclines/therapeutic use , Tetracyclines/administration & dosage , Tetracyclines/pharmacology , Male , Female , Middle Aged , Adult , Area Under Curve , Staphylococcus aureus/drug effects , Skin Diseases, Bacterial/drug therapy , Skin Diseases, Bacterial/microbiology , Aged , Staphylococcal Skin Infections/drug therapy , Staphylococcal Skin Infections/microbiology , Administration, Oral , Drug Administration Schedule
10.
Infect Immun ; 92(8): e0013324, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-38953668

ABSTRACT

Staphylococcus aureus α-hemolysin (Hla) is a pore-forming toxin critical for the pathogenesis of skin and soft tissue infections, which causes the pathognomonic lesion of cutaneous necrosis (dermonecrosis) in mouse models. To determine the mechanism by which dermonecrosis develops during S. aureus skin infection, mice were given control serum, Hla-neutralizing antiserum, or an inhibitor of Hla receptor [A-disintegrin and metalloprotease 10 (ADAM10) inhibitor] followed by subcutaneous infection by S. aureus, and the lesions were evaluated using immunohistochemistry and immunofluorescence. Hla induced apoptosis in the vascular endothelium at 6 hours post-infection (hpi), followed by apoptosis in keratinocytes at 24 hpi. The loss of vascular endothelial (VE)-cadherin expression preceded the loss of epithelial-cadherin expression. Hla also induced hypoxia in the keratinocytes at 24 hpi following vascular injury. Treatment with Hla-neutralizing antibody or ADAM10 inhibitor attenuated early cleavage of VE-cadherin, cutaneous hypoxia, and dermonecrosis. These findings suggest that Hla-mediated vascular injury with cutaneous hypoxia underlies the pathogenesis of S. aureus-induced dermonecrosis.


Subject(s)
ADAM10 Protein , Bacterial Toxins , Cadherins , Hemolysin Proteins , Keratinocytes , Necrosis , Staphylococcus aureus , Animals , Hemolysin Proteins/metabolism , Hemolysin Proteins/toxicity , Mice , Bacterial Toxins/toxicity , Bacterial Toxins/metabolism , Staphylococcus aureus/pathogenicity , Keratinocytes/microbiology , Keratinocytes/metabolism , ADAM10 Protein/metabolism , Cadherins/metabolism , Apoptosis , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Antigens, CD/metabolism , Membrane Proteins/metabolism , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/pathology , Staphylococcal Skin Infections/immunology , Skin/pathology , Skin/microbiology , Female , Endothelium, Vascular/pathology , Endothelium, Vascular/microbiology , Endothelium, Vascular/metabolism , Staphylococcal Infections/microbiology , Staphylococcal Infections/immunology , Staphylococcal Infections/pathology , Disease Models, Animal
11.
Antimicrob Resist Infect Control ; 13(1): 68, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38918863

ABSTRACT

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of mortality due to bacterial antimicrobial resistance. While S. aureus is common in skin and soft tissue infections (SSTI) in Africa, data on MRSA rates are scarce and reports vary widely across the continent (5%-80%). In this study, we describe the proportion of MRSA causing SSTI in Lambaréné, Gabon, over an 11-year period. METHODS: We retrospectively analyzed data from 953 bacterial specimens collected from inpatients and outpatients with SSTI at the Albert Schweitzer Hospital, Lambaréné, Gabon, between 2009 and 2019. We determined temporal changes in the prevalence of MRSA and identified risk factors for SSTI with MRSA. RESULTS: 68% of all specimens with bacterial growth yielded S. aureus (n = 499/731), of which 7% (36/497) with antimicrobial susceptibility testing were identified as MRSA. Age above 18 years, admission to the surgical ward, and deep-seated infections were significantly associated with MRSA as the causative agent. After an initial decline from 7% in 2009, there was a marked increase in the proportion of MRSA among all S. aureus from SSTI from 3 to 20% between 2012 and 2019. The resistance rate to erythromycin was significantly higher in MRSA than in methicillin-susceptible S. aureus (73% vs. 10%), and clindamycin resistance was detected exclusively in MRSA isolates (8%). CONCLUSION: The increasing proportion of MRSA causing SSTI over the 11-year period contrasts with many European countries where MRSA is on decline. Continuous surveillance of MRSA lineages in the hospital and community along with antibiotic stewardship programs could address the increasing trend of MRSA.


Subject(s)
Anti-Bacterial Agents , Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Soft Tissue Infections , Humans , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Methicillin-Resistant Staphylococcus aureus/drug effects , Gabon/epidemiology , Soft Tissue Infections/microbiology , Soft Tissue Infections/epidemiology , Retrospective Studies , Male , Female , Adult , Adolescent , Middle Aged , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Young Adult , Prevalence , Child , Risk Factors , Staphylococcal Skin Infections/epidemiology , Staphylococcal Skin Infections/microbiology , Staphylococcal Infections/epidemiology , Staphylococcal Infections/microbiology , Child, Preschool , Aged , Infant
12.
Biochem Pharmacol ; 227: 116404, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38945279

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA), a notorious bacterium with high drug resistance and easy recurrence after surgery, has posed significant clinical treatment challenges. In the current scarcity of new antibiotics, the identification of adjuvants to existing antibiotics is a promising approach to combat infections caused by multidrug-resistant Gram-positive bacteria. The in vitro synergy test, which included a MIC assay, time-kill curve, antimicrobial susceptibility testing, and live/dead bacteria staining assay, revealed that laurocapram, a widely used chemical transdermal enhancer, could potentiate the antibacterial activity of cephalosporins against MRSA. In vitro, laurocapram combined with cefixime showed an excellent synergistic activity against MRSA (FICI = 0.28 ± 0.00). In addition, the combination of laurocapram and cefixime may inhibited the formation of MRSA biofilm and caused cell membrane damage. Following that, we discovered that combining laurocapram with cefixime could alleviate the symptoms of mice in the MRSA skin infection model and the MRSA pneumonia model. In conclusion, laurocapram is a promising and low-cost antibacterial adjuvant, providing a new strategy for further exploring the use of lower doses of cephalosporins to combat MRSA infection.


Subject(s)
Anti-Bacterial Agents , Cephalosporins , Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Methicillin-Resistant Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Cephalosporins/administration & dosage , Cephalosporins/pharmacology , Mice , Female , Administration, Cutaneous , Drug Synergism , Mice, Inbred BALB C , Staphylococcal Skin Infections/drug therapy , Staphylococcal Skin Infections/microbiology , Staphylococcal Infections/drug therapy
13.
Acta Derm Venereol ; 104: adv34882, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38860624

ABSTRACT

Patients with atopic dermatitis (AD) are more likely than healthy individuals to harbour Staphylococcus aureus on their skin. Superantigens (SAgs) produced by specific S. aureus strains may contribute to AD-associated skin inflammation. The present study compared the prevalence and types of SAg-encoding genes between S. aureus isolated from patients with AD and from  controls, and within the AD group between isolates from different sampling sites (lesional skin, non-lesional skin, and nares). This retrospective case-control study extracted data from 2 previous studies that examined S. aureus using whole-genome sequencing. The 138 S. aureus isolates obtained from 71 AD patients contained 349 SAg-encoding genes; 22 (6.3%) were found in isolates from nares (0.4 ± 0.6 genes per isolate), 99 (28.4%) in isolates from non-lesional skin (3.7 ± 3.9), and 228 (65.3%) in isolates from lesional skin (4.2 ± 4.5). S. aureus (n = 101) from the control group contained 594 SAg-encoding genes (5.9 ± 4.2). Of the S. aureus isolated from lesional AD skin, 69% carried at least 1 gene encoding SAg compared with 33% of AD nasal isolates. SAg could be a factor in the pathogenesis of a subset of AD patients.


Subject(s)
Dermatitis, Atopic , Skin , Staphylococcus aureus , Superantigens , Humans , Dermatitis, Atopic/microbiology , Superantigens/genetics , Staphylococcus aureus/genetics , Staphylococcus aureus/isolation & purification , Retrospective Studies , Skin/microbiology , Male , Female , Case-Control Studies , Adult , Staphylococcal Skin Infections/microbiology , Middle Aged , Young Adult
14.
Sci Rep ; 14(1): 12919, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38839902

ABSTRACT

People who inject drugs are frequently colonized with Staphylococcus aureus and have an increased risk for skin and soft tissue infections. This longitudinal study aims to describe S. aureus carriage in this group and the risk for infections during a 1-year follow-up. We included 61 participants from the Malmö Needle Exchange Program. Mapping of S. aureus carriage was conducted by screening cultures every third month and S. aureus growth was semi-quantified. Data regarding infections and living conditions were collected from structured interviews. Statistics included univariate analysis with the Fischer's exact test, univariate logistic regression and multivariate logistic regression. S. aureus carriage was detected in 46-63% of participants, and 75% reported one or more infections during the study period. Self-reported infections were associated with carriage in perineum (OR 5.08 [95% CI 1.45-17.73]), in skin lesions (OR 1.48 [95% CI 1.21-1.81]), and unstable housing situation (OR 12.83 [95% CI 1.56-105.81]). Thus, people who inject drugs are frequent carriers of S. aureus and report a surprisingly high prevalence of skin and soft tissue infections. Homeless people and those with skin carriage seem to be at highest risk. Effective clinical interventions are needed, aiming at preventing infections in this vulnerable group.


Subject(s)
Carrier State , Soft Tissue Infections , Staphylococcus aureus , Substance Abuse, Intravenous , Humans , Soft Tissue Infections/epidemiology , Soft Tissue Infections/microbiology , Male , Longitudinal Studies , Female , Staphylococcus aureus/isolation & purification , Adult , Prevalence , Substance Abuse, Intravenous/complications , Substance Abuse, Intravenous/epidemiology , Carrier State/epidemiology , Carrier State/microbiology , Staphylococcal Skin Infections/epidemiology , Staphylococcal Skin Infections/microbiology , Middle Aged , Staphylococcal Infections/epidemiology , Staphylococcal Infections/microbiology , Risk Factors
15.
J Allergy Clin Immunol ; 154(2): 355-374, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38734386

ABSTRACT

BACKGROUND: The contribution of Staphylococcus aureus to the exacerbation of atopic dermatitis (AD) is widely documented, but its role as a primary trigger of AD skin symptoms remains poorly explored. OBJECTIVES: This study sought to reappraise the main bacterial factors and underlying immune mechanisms by which S aureus triggers AD-like inflammation. METHODS: This study capitalized on a preclinical model, in which different clinical isolates were applied in the absence of any prior experimental skin injury. RESULTS: The development of S aureus-induced dermatitis depended on the nature of the S aureus strain, its viability, the concentration of the applied bacterial suspension, the production of secreted and nonsecreted factors, as well as the activation of accessory gene regulatory quorum sensing system. In addition, the rising dermatitis, which exhibited the well-documented AD cytokine signature, was significantly inhibited in inflammasome adaptor apoptosis-associated speck-like protein containing a CARD domain- and monocyte/macrophage-deficient animals, but not in T- and B-cell-deficient mice, suggesting a major role for the innate response in the induction of skin inflammation. However, bacterial exposure generated a robust adaptive immune response against S aureus, and an accumulation of S aureus-specific γδ and CD4+ tissue resident memory T cells at the site of previous dermatitis. The latter both contributed to worsen the flares of AD-like dermatitis on new bacteria exposures, but also, protected the mice from persistent bacterial colonization. CONCLUSIONS: These data highlight the induction of unique AD-like inflammation, with the generation of proinflammatory but protective tissue resident memory T cells in a context of natural exposure to pathogenic S aureus strains.


Subject(s)
Dermatitis, Atopic , Memory T Cells , Skin , Staphylococcal Infections , Staphylococcus aureus , Animals , Dermatitis, Atopic/immunology , Dermatitis, Atopic/microbiology , Staphylococcus aureus/immunology , Mice , Skin/immunology , Skin/microbiology , Skin/pathology , Staphylococcal Infections/immunology , Memory T Cells/immunology , Mice, Inbred C57BL , Disease Models, Animal , Female , Cytokines/metabolism , Cytokines/immunology , Symptom Flare Up , Staphylococcal Skin Infections/immunology , Staphylococcal Skin Infections/microbiology
16.
Am J Infect Control ; 52(8): 977-980, 2024 08.
Article in English | MEDLINE | ID: mdl-38763430

ABSTRACT

We identified a high prevalence (46.4%) of wound colonization with methicillin-resistant Staphylococcus aureus (MRSA) in patients hospitalized in a center devoted to the treatment of cutaneous tropical diseases in Benin. The proportion of MRSA among S aureus isolates was 54.3%. Thirty percent of these MRSA were identified in outpatients. The analysis of pulsed-field gel electrophoresis demonstrated an important diversity of strains but also identified 8 small clusters containing between 2 and 4 isolates suggesting cross-transmission.


Subject(s)
Methicillin-Resistant Staphylococcus aureus , Rural Population , Staphylococcal Infections , Humans , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Benin/epidemiology , Male , Female , Staphylococcal Infections/drug therapy , Staphylococcal Infections/epidemiology , Staphylococcal Infections/microbiology , Adult , Middle Aged , Adolescent , Prevalence , Young Adult , Child , Electrophoresis, Gel, Pulsed-Field , Wound Infection/microbiology , Wound Infection/epidemiology , Wound Infection/drug therapy , Aged , Carrier State/microbiology , Carrier State/epidemiology , Child, Preschool , Neglected Diseases/microbiology , Neglected Diseases/epidemiology , Infant , Cross Infection/microbiology , Cross Infection/epidemiology , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/drug therapy , Staphylococcal Skin Infections/epidemiology , Aged, 80 and over
17.
Commun Biol ; 7(1): 572, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38750133

ABSTRACT

Long-chain fatty acids with antimicrobial properties are abundant on the skin and mucosal surfaces, where they are essential to restrict the proliferation of opportunistic pathogens such as Staphylococcus aureus. These antimicrobial fatty acids (AFAs) elicit bacterial adaptation strategies, which have yet to be fully elucidated. Characterizing the pervasive mechanisms used by S. aureus to resist AFAs could open new avenues to prevent pathogen colonization. Here, we identify the S. aureus lipase Lip2 as a novel resistance factor against AFAs. Lip2 detoxifies AFAs via esterification with cholesterol. This is reminiscent of the activity of the fatty acid-modifying enzyme (FAME), whose identity has remained elusive for over three decades. In vitro, Lip2-dependent AFA-detoxification was apparent during planktonic growth and biofilm formation. Our genomic analysis revealed that prophage-mediated inactivation of Lip2 was rare in blood, nose, and skin strains, suggesting a particularly important role of Lip2 for host - microbe interactions. In a mouse model of S. aureus skin colonization, bacteria were protected from sapienic acid (a human-specific AFA) in a cholesterol- and lipase-dependent manner. These results suggest Lip2 is the long-sought FAME that exquisitely manipulates environmental lipids to promote bacterial growth in otherwise inhospitable niches.


Subject(s)
Fatty Acids , Lipase , Staphylococcus aureus , Staphylococcus aureus/metabolism , Fatty Acids/metabolism , Animals , Mice , Lipase/metabolism , Lipase/genetics , Humans , Staphylococcal Infections/microbiology , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Biofilms/growth & development , Female , Staphylococcal Skin Infections/microbiology
18.
JCI Insight ; 9(9)2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38716729

ABSTRACT

Atopic dermatitis (AD) is an inflammatory skin condition with a childhood prevalence of up to 25%. Microbial dysbiosis is characteristic of AD, with Staphylococcus aureus the most frequent pathogen associated with disease flares and increasingly implicated in disease pathogenesis. Therapeutics to mitigate the effects of S. aureus have had limited efficacy and S. aureus-associated temporal disease flares are synonymous with AD. An alternative approach is an anti-S. aureus vaccine, tailored to AD. Experimental vaccines have highlighted the importance of T cells in conferring protective anti-S. aureus responses; however, correlates of T cell immunity against S. aureus in AD have not been identified. We identify a systemic and cutaneous immunological signature associated with S. aureus skin infection (ADS.aureus) in a pediatric AD cohort, using a combined Bayesian multinomial analysis. ADS.aureus was most highly associated with elevated cutaneous chemokines IP10 and TARC, which preferentially direct Th1 and Th2 cells to skin. Systemic CD4+ and CD8+ T cells, except for Th2 cells, were suppressed in ADS.aureus, particularly circulating Th1, memory IL-10+ T cells, and skin-homing memory Th17 cells. Systemic γδ T cell expansion in ADS.aureus was also observed. This study suggests that augmentation of protective T cell subsets is a potential therapeutic strategy in the management of S. aureus in AD.


Subject(s)
Dermatitis, Atopic , Staphylococcal Skin Infections , Staphylococcus aureus , Dermatitis, Atopic/immunology , Dermatitis, Atopic/microbiology , Humans , Staphylococcus aureus/immunology , Child , Female , Staphylococcal Skin Infections/immunology , Staphylococcal Skin Infections/microbiology , Male , Child, Preschool , Skin/microbiology , Skin/immunology , Skin/pathology , Chemokine CXCL10/immunology , Chemokine CXCL10/metabolism , Th1 Cells/immunology , Th2 Cells/immunology , Th17 Cells/immunology , Bayes Theorem , CD8-Positive T-Lymphocytes/immunology , Interleukin-10/metabolism , Interleukin-10/immunology , Intraepithelial Lymphocytes/immunology , Antigens, Differentiation, T-Lymphocyte , Membrane Glycoproteins
19.
Euro Surveill ; 29(19)2024 May.
Article in English | MEDLINE | ID: mdl-38726693

ABSTRACT

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.


Subject(s)
Drug Resistance, Bacterial , Fusidic Acid , Mupirocin , Staphylococcal Skin Infections , Staphylococcus aureus , Belgium/epidemiology , Drug Resistance, Bacterial/genetics , Drug Resistance, Multiple, Bacterial/genetics , Fusidic Acid/pharmacology , Genome, Bacterial/genetics , Impetigo/microbiology , Mupirocin/pharmacology , Staphylococcal Skin Infections/epidemiology , Staphylococcal Skin Infections/microbiology , Staphylococcus aureus/drug effects , Staphylococcus aureus/genetics , Staphylococcus aureus/isolation & purification , Virulence Factors/genetics , Humans
20.
Int J Biol Macromol ; 271(Pt 1): 132577, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38795887

ABSTRACT

Staphylococcus aureus is a pathogen widely involved in wound infection due to its ability to release several virulence factors that impair the skin healing process, as well as its mechanism of drug resistance. Herein, sodium alginate and chitosan were combined to produce a hydrogel for topical delivery of neomycin to combat S. aureus associated with skin complications. The hydrogel was formulated by combining sodium alginate (50 mg/mL) and chitosan (50 mg/mL) solutions in a ratio of 9:1 (HBase). Neomycin was added to HBase to achieve a concentration of 0.4 mg/mL (HNeo). The incorporation of neomycin into the product was confirmed by scanning electron microscopy, FTIR and TGA analysis. The hydrogels produced are homogeneous, have a high swelling capacity, and show biocompatibility using erythrocytes and fibroblasts as models. The formulations showed physicochemical and pharmacological stability for 60 days at 4 ± 2 °C. HNeo totally inhibited the growth of S. aureus after 4 h. The antimicrobial effects were confirmed using ex vivo (porcine skin) and in vivo (murine) wound infection models. Furthermore, the HNeo-treated mice showed lower severity scores than those treated with HBase. Taken together, the obtained results present a new low-cost bioproduct with promising applications in treating infected wounds.


Subject(s)
Alginates , Anti-Bacterial Agents , Chitosan , Hydrogels , Neomycin , Staphylococcus aureus , Chitosan/chemistry , Chitosan/pharmacology , Alginates/chemistry , Alginates/pharmacology , Hydrogels/chemistry , Hydrogels/pharmacology , Staphylococcus aureus/drug effects , Animals , Mice , Neomycin/pharmacology , Neomycin/chemistry , Neomycin/administration & dosage , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Staphylococcal Infections/drug therapy , Staphylococcal Skin Infections/drug therapy , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/pathology , Drug Carriers/chemistry , Skin/drug effects , Skin/microbiology
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