RESUMEN
Aim: Polymyxin B (PMB) is one of the few therapeutic options for treating infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB). However, the emergence of PMB-resistant CR-GNB strains has prompted the exploration of antibiotic adjuvants as potential therapeutic avenues. Thus, this study evaluates the potential of 3,5-dinitrobenzoic acid derivatives (DNH01, DNH11, DNH13 and DNH20) and isoniazid-N-acylhydrazones (INZ1-7, INZ9 and INZ11) as adjuvants to enhance PMB efficacy against CR-GNB.Materials & methods: MIC, MBC and drug combination assays were conducted using multidrug-resistant clinical isolates of Enterobacterales and Acinetobacter baumannii. In addition, the effects of PMB and PMB + DNH derivatives were assessed through flow cytometry and scanning electron microscopy (SEM).Results: DNH01, DNH11 and DNH20, unlike the INH-acylhydrazones, significantly restored PMB activity (MIC ≤ 2 µg/ml) in 80% of the tested isolates. Flow cytometry and SEM assays confirmed that DNH derivatives rescued the activity of PMB, yielding results comparable to those expected for PMB alone but at 256-fold lower concentrations.Conclusion: These findings suggest DNH derivatives hold substantial promise as PMB adjuvants to combat PMB-resistant CR-GNB infections.
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Asunto(s)
Antibacterianos , Carbapenémicos , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Polimixina B , Polimixina B/farmacología , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Carbapenémicos/farmacología , Humanos , Acinetobacter baumannii/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Adyuvantes Farmacéuticos/farmacología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Sinergismo FarmacológicoRESUMEN
Due to the significant shortage of therapeutic options for carbapenem-resistant Enterobacterales (CRE) infections, new drugs or therapeutic combinations are urgently required. We show in this study that (-)-camphene-based thiosemicarbazide (TSC) may act synergistically with polymyxin B (PMB) against CRE, rescuing the activity of this antimicrobial. With the specific aim of a better molecular understanding of this effect caused by the presence of TSC, theoretical calculations were also performed in this study. Based on these findings, it is concluded that the presence of TSC moieties contributes to significant changes in the hydrogen atom charge of PMB structure, which trend more positives for the PMB/TSC system studied. This could lead to the formation of stronger hydrogen bonds in the Enterobacterales active site and, thus contribute to a molecular understanding of the PMB rescue of activity promoted by the presence of TSC moiety. As such, the clinical potential of these drug combinations requires further evaluation.
Asunto(s)
Carbapenémicos , Polimixina B , Antibacterianos/farmacología , Monoterpenos Bicíclicos , Carbapenémicos/farmacología , Combinación de Medicamentos , Hidrógeno , Pruebas de Sensibilidad Microbiana , Polimixina B/farmacologíaRESUMEN
Yeasts of the genera Candida and Saccharomyces are opportunist pathogens and cause oral lesions, especially in immunocompromised patients. This study assessed yeasts isolated from chronic kidney patients undergoing haemodialysis for their adhesion capacity, biofilm formation and susceptibility to antifungal agents. Ten isolates of Candida spp. and one isolate of Saccharomyces cerevisiae were tested for adhesion to buccal epithelial cells (BECs), adhesion and formation of biofilm in artificial saliva and their susceptibility profile to antifungal agents. Adhesion and biofilm formation were undertaken in polystyrene plates with artificial saliva, whilst susceptibility to antifungal agents was evaluated by broth microdilution. Candida parapsilosis had the highest adhesion index in BECs (154.55 ± 22.13) and Candida rugosa was the species with the highest adhesion capacity (18â398â Abs cm(-2)) in abiotic surface with artificial saliva. Candida albicans provided the greatest biofilm formation (2035â Abs cm(-2) ± 0.09) but was revealed to be susceptible to the five antifungal agents under analysis. However, some non-albicans Candida isolates showed a lower susceptibility for the antifungal agents itraconazole, fluconazole and voriconazole. All of the species were sensitive to amphotericin B and nystatin. The current analysis showed that yeasts isolated from the mouth of chronic kidney patients undergoing haemodialysis varied significantly with regard to their capacity for adherence, biofilm formation and susceptibility to antifungal agents, underscoring the high virulence of non-albicans Candida species.