Skin dysbiosis and Cutibacterium acnes biofilm in inflammatory acne lesions of adolescents

Acne vulgaris is a common inflammatory disorder affecting more than 80% of young adolescents. Cutibacterium acnes plays a role in the pathogenesis of acne lesions, although the mechanisms are poorly understood. The study aimed to explore the microbiome at different skin sites in adolescent acne and the role of biofilm production in promoting the growth and persistence of C. acnes isolates. Microbiota analysis showed a significantly lower alpha diversity in inflammatory lesions (LA) than in non-inflammatory (NI) lesions of acne patients and healthy subjects (HS). Differences at the species level were driven by the overabundance of C. acnes on LA than NI and HS. The phylotype IA1 was more represented in the skin of acne patients than in HS. Genes involved in lipids transport and metabolism, as well as potential virulence factors associated with host-tissue colonization, were detected in all IA1 strains independently from the site of isolation. Additionally, the IA1 isolates were more efficient in early adhesion and biomass production than other phylotypes showing a significant increase in antibiotic tolerance. Overall, our data indicate that the site-specific dysbiosis in LA and colonization by virulent and highly tolerant C. acnes phylotypes may contribute to acne development in a part of the population, despite the universal carriage of the microorganism. Moreover, new antimicrobial agents, specifically targeting biofilm-forming C. acnes, may represent potential treatments to modulate the skin microbiota in acne

In vitro characterization, ADME analysis, and histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains

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Modulating the skin mycobiome-bacteriome and treating seborrheic dermatitis with a probiotic-enriched oily suspension

Abstract Seborrheic dermatitis (SD) affects 2–5% of the global population, with imbalances in the skin microbiome implicated in its development. This study assessed the impact of an oily suspension containing Lactobacillus crispatus P17631 and Lacticaseibacillus paracasei I1688 (termed EUTOPLAC) on SD symptoms and the skin mycobiome-bacteriome modulation. 25 SD patients were treated with EUTOPLAC for a week. Symptom severity and skin mycobiome-bacteriome changes were measured at the start of the treatment (T0), after seven days (T8), and three weeks post-treatment (T28). Results indicated symptom improvement post-EUTOPLAC, with notable reductions in the Malassezia genus. Concurrently, bacterial shifts were observed, including a decrease in Staphylococcus and an increase in Lactobacillus and Lacticaseibacillus. Network analysis highlighted post-EUTOPLAC instability in fungal and bacterial interactions, with increased negative correlations between Malassezia and Lactobacillus and Lacticaseibacillus genera. The study suggests EUTOPLAC's potential as a targeted SD treatment, reducing symptoms and modulating the mycobiome-bacteriome composition

Role of extracellular DNA in Dalbavancin activity against Methicillin-Resistant Staphylococcus aureus (MRSA) biofilms in patients with skin and soft tissue infections

Methicillin-resistant Staphylococcus aureus (MRSA) has become the leading cause of skin and soft tissue infections (SSTIs). Biofilm production further complicates patient treatment, contributing to increased bacterial persistence and antibiotic tolerance. The study aimed to explore the efficacy of different antibiotics on biofilm-producing MRSA isolated from patients with SSTI. A total of 32 MRSA strains were collected from patients with SSTI. The MIC and minimal biofilm eradication concentration (MBEC) were measured in planktonic and biofilm growth. The study showed that dalbavancin, linezolid, and vancomycin all inhibited MRSA growth at their EUCAST susceptible breakpoint. Of the MRSA strains, 87.5% (n = 28) were strong biofilm producers (SBPs), while only 12.5% (n = 4) were weak biofilm producers (WBPs). The MBEC90 values for dalbavancin were significantly lower than those of linezolid and vancomycin in all tested strains. We also found that extracellular DNA (eDNA) contributes to the initial microbial attachment and biofilm formation. The amount of eDNA differed among MRSA strains and was significantly higher in those isolates with high dalbavancin and vancomycin tolerance. Exogenously added DNA increased the MBEC90 and protection of biofilm cells from dalbavancin activity. Of note, the relative abundance of eDNA was higher in MRSA biofilms exposed to MBEC90 dalbavancin than in untreated MRSA biofilms and those exposed to sub-MIC90. Overall, dalbavancin was the most active antibiotic against MRSA biofilms at concentrations achievable in the human serum. Moreover, the evidence of a drug-related increase of eDNA and its contribution to antimicrobial drug tolerance reveals novel potential targets for antibiofilm strategies against MRSA. IMPORTANCE Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) worldwide. In addition, methicillin-resistant S. aureus (MRSA) is increasingly frequent in postoperative infections and responsible for a large number of hospital readmissions and deaths. Biofilm formation by S. aureus is a primary risk factor in SSTIs, due to a higher antibiotic tolerance. Our study showed that the biofilm-forming capacity varied among MRSA strains, although strong biofilm producers were significantly more abundant than weak biofilm producer strains. Notably, dalbavancin demonstrated a potent antibiofilm activity at concentrations achievable in human serum. Nevertheless, dalbavancin activity was affected by an increased concentration of extracellular DNA in the biofilm matrix. This study provides novel insight for designing more targeted therapeutic strategies against MRSA and to prevent or eradicate harmful biofilms.Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) worldwide. In addition, methicillin-resistant S. aureus (MRSA) is increasingly frequent in postoperative infections and responsible for a large number of hospital readmissions and deaths

Focused library of phenyl-fused macrocyclic amidinoureas as antifungal agents

The rise of antimicrobial-resistant phenotypes and the spread of the global pandemic of COVID-19 are worsening the outcomes of hospitalized patients for invasive fungal infections. Among them, candidiases are seriously worrying, especially since the currently available drug armamentarium is extremely limited. We recently reported a new class of macrocyclic amidinoureas bearing a guanidino tail as promising antifungal agents. Herein, we present the design and synthesis of a focused library of seven derivatives of macrocyclic amidinoureas, bearing a second phenyl ring fused with the core. Biological activity evaluation shows an interesting antifungal profile for some compounds, resulting to be active on a large panel of Candida spp. and C. neoformans. PAMPA experiments for representative compounds of the series revealed a low passive diffusion, suggesting a membrane-based mechanism of action or the involvement of active transport systems. Also, compounds were found not toxic at high concentrations, as assessed through MTT assays.14n

Depressive Anxiety Symptoms in Hospitalized Children with Chronic Illness during the First Italian COVID-19 Lockdown

COVID-19 is continuing to spread around the world, having a direct impact on people’s daily lives and health. Although the knowledge of the impact of the COVID-19 pandemic on mental health in the general population is now well established, there is less information on its effect on specific and vulnerable populations, such as children with chronic illness (CI). We conducted a multi-centered cross-sectional study among pediatric patients in six public children’s hospitals in Italy during the first lockdown, with the aim of assessing the proportion of children with CI presenting anxiety and depressive symptoms, and the clinical and demographic characteristics affecting such symptomatology. We included children with at least one chronic condition, with no cognitive delay, aged between 11 and 18 years. Brief standardized questionnaires were administered during medical scheduled visits to screen anxiety and depressive symptoms. We found a very high proportion of children showing mild to severe depressive and anxiety symptomatology (approximately 68% and 63%, respectively). Our results highlight the need of ensuring tailored psychological interventions to protect children with CI from the effect of the pandemic (and related restrictive measures such as quarantine and social distancing), with the final aim of promoting mental health and psychological well-being in this vulnerable population

In vitro characterization, ADME analysis, histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains

BACKGROUND: Among the opportunistic fungi, Candida species represent one of the most common causes of nosocomial bloodstream infections. The large use of antifungal agents, most of them launched on the market more than twenty years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. In the last years, we described a novel class of antifungal macrocyclic compounds bearing an amidinourea moiety, highly active against various azole-resistant Candida strains. OBJECTIVE: In this study, one representative of this family, compound BM1, has been investigated on its in vitro activity against various Candida species, including C. auris isolates, its interaction with the ABC transporter CDR6 and its in vivo distribution and safety. METHODS: In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) have been used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis have been exploited to evaluate in vivo toxicology, pharmacokinetics, and distribution. RESULTS: Our research highlights the low in vivo toxicity profile of BM1, its affinity for the renal system in rats and its good absorption, distribution, metabolism, and excretion (ADME) features. Our compound preserves a potent activity also against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains. CONCLUSIONS: We confirmed low MICs against several Candida species, including preliminary data versus C. auris. The good ADME and biochemical characteristics make BM1 suitable and safe for daily administration and particularly indicated to treat renal infections. These data make BM1 and its derivatives a novel promising antifungal class