Histatin-5 induces the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisae.

BACKGROUND: Candidiasis is a major opportunistic fungal infection in humans. The low number of antifungal drugs available to treat Candida infections and the increasing incidence of multidrug resistant (MDR) strains point to an urgent need of identifying new therapeutic options. The role of salivary components can provide insights for the development of new methodologies of control. OBJECTIVE: The aim of this study was to evaluate the ability of histatin-5, a constitutive immunological peptide present in saliva, in reversing fungal MDR phenotype, using a resistant Saccharomyces cerevisiae strain as model of study. RESULTS: A total of 2.5µg and 5µg of histatin-5 revealed to be able to chemosensitize (to revert antifungal resistance) a MDR strain to fluconazole impairing its intrinsic resistance. The presence of histatin-5 decreased the strain growth when associated to fluconazole, and also assisted in the retention of rhodamine 6G within cell cytoplasm. The ATPase activity of Pdr5p, an ABC efflux transporter, was significantly reduced up to 65% within physiological concentration of the peptide. CONCLUSION: Results revealed that histatin-5 is able to revert MDR phenotype and may be considered a potential alternative MDR inhibitor. Since Pdr5p is homologous to Candida albicans CaCdr1p and CaCdr2p, data obtained might be extrapolated to these transporters, inferring that associating fluconazole and histatin-5 may be a useful tool to circumvent failure treatments of infections caused by Candida MDR strains.

Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole.

Invasive Candida albicans infections are a serious health threat for immunocompromised individuals. Fluconazole is most commonly used to treat these infections, but resistance due to the overexpression of multidrug efflux pumps is of grave concern. This study evaluated the ability of five synthetic organotellurium compounds to reverse the fluconazole resistance of C. albicans clinical isolates. Compounds 1 to 4, at <10 µg/ml, ameliorated the fluconazole resistance of Saccharomyces cerevisiae strains overexpressing the major C. albicans multidrug efflux pumps Cdr1p and Mdr1p, whereas compound 5 only sensitized Mdr1p-overexpressing strains to fluconazole. Compounds 1 to 4 also inhibited efflux of the fluorescent substrate rhodamine 6G and the ATPase activity of Cdr1p, whereas all five of compounds 1 to 5 inhibited Nile red efflux by Mdr1p. Interestingly, all five compounds demonstrated synergy with fluconazole against efflux pump-overexpressing fluconazole-resistant C. albicans clinical isolates, isolate 95-142 overexpressing CDR1 and CDR2, isolate 96-25 overexpressing MDR1 and ERG11, and isolate 12-99 overexpressing CDR1, CDR2, MDR1, and ERG11 Overall, organotellurium compounds 1 and 2 were the most promising fluconazole chemosensitizers of fluconazole-resistant C. albicans isolates. Our data suggest that these novel organotellurium compounds inhibit pump efflux by two very important and distinct families of fungal multidrug efflux pumps: the ATP-binding cassette transporter Cdr1p and the major facilitator superfamily transporter Mdr1p.

Gait Speed as a Predictor of Respiratory Muscle Function, Strength, and Frailty Syndrome in Community-Dwelling Elderly People.

BACKGROUND: Gait speed is considered a predictor of adverse health outcomes and functional decline in the elderly. This decline is also identified in respiratory muscles. OBJECTIVE: To assess the impact of gait speed in maximal inspiratory pressure, maximal expiratory pressure, handgrip strength, and the different types of frailty syndrome in community-dwelling elderly people. DESIGN: Cross-sectional study. PARTICIPANTS: Women (aged ≥ 65 years) were classified into different frailty phenotypes (n = 106). MEASUREMENTS: Gait speed (10 m), handgrip strength (Jamar dynamometer), and maximum inspiratory and expiratory pressures (GerAr manovacuometer, MV-150/300 model) were measured. Linear regression analyses were conducted to determine the influence of gait speed and age on handgrip strength, maximal inspiratory pressure, and maximal expiratory pressure. Logistic regression was performed to assess the influence of gait speed and frailty age (α = 0.05). RESULTS: A total of 106 elderly women participated in the study (73.96 ± 6.91 years). Thirty-two subjects were not frail, 42 were pre-frail, and 32 were frail. Gait speed and age significantly predicted handgrip strength and frailty (p < 0.05). In the multivariate model, gait speed had the greatest contribution, while age lost statistical significance. Regarding maximal inspiratory and maximal expiratory pressures, gait speed and age were significant explanatory variables (p < 0.05). In the multivariate model, gait speed lost statistical significance to predict maximal inspiratory pressure. CONCLUSION: Gait speed was confirmed to be a predictor of some health outcomes, including respiratory muscle function. The results suggest that interventions to increase gait speed may contribute to improve respiratory function and muscle strength, and decrease the risk of frailty among elderly people.