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1.
mBio ; 14(4): e0047923, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37326546

RESUMO

Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or patients in intensive care units. The limited antifungal arsenal and emerging multidrug-resistant species necessitate the development of new therapies. One strategy for combating drug-resistant pathogens is the administration of molecules that restore fungal susceptibility to approved drugs. Accordingly, we carried out a screen to identify small molecules that could restore the susceptibility of pathogenic Candida species to azole antifungals. This screening effort led to the discovery of novel 1,4-benzodiazepines that restore fluconazole susceptibility in resistant isolates of Candida albicans, as evidenced by 100-1,000-fold potentiation of fluconazole activity. This potentiation effect was also observed in azole-tolerant strains of C. albicans and in other pathogenic Candida species. The 1,4-benzodiazepines selectively potentiated different azoles, but not other approved antifungals. A remarkable feature of the potentiation was that the combination of the compounds with fluconazole was fungicidal, whereas fluconazole alone is fungistatic. Interestingly, the potentiators were not toxic to C. albicans in the absence of fluconazole, but inhibited virulence-associated filamentation of the fungus. We found that the combination of the potentiators and fluconazole significantly enhanced host survival in a Galleria mellonella model of systemic fungal infection. Taken together, these observations validate a strategy wherein small molecules can restore the activity of highly used anti-infectives that have lost potency. IMPORTANCE In the last decade, we have been witnessing a higher incidence of fungal infections, due to an expansion of the fungal species capable of causing disease (e.g., Candida auris), as well as increased antifungal drug resistance. Among human fungal pathogens, Candida species are a leading cause of invasive infections and are associated with high mortality rates. Infections by these pathogens are commonly treated with azole antifungals, yet the expansion of drug-resistant isolates has reduced their clinical utility. In this work, we describe the discovery and characterization of small molecules that potentiate fluconazole and restore the susceptibility of azole-resistant and azole-tolerant Candida isolates. Interestingly, the potentiating 1,4-benzodiazepines were not toxic to fungal cells but inhibited their virulence-associated filamentous growth. Furthermore, combinations of the potentiators and fluconazole decreased fungal burdens and enhanced host survival in a Galleria mellonella model of systemic fungal infections. Accordingly, we propose the use of novel antifungal potentiators as a powerful strategy for addressing the growing resistance of fungi to clinically approved drugs.


Assuntos
Antifúngicos , Micoses , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Azóis/farmacologia , Preparações Farmacêuticas , Testes de Sensibilidade Microbiana , Candida albicans , Micoses/tratamento farmacológico , Farmacorresistência Fúngica , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico
2.
Exp Eye Res ; 181: 325-345, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30296412

RESUMO

Oxidative cleavage of docosahexaenoate (DHA) in retinal pigmented epithelial (RPE) cells produces 4-hydroxy-7-oxohept-5-enoic acid (HOHA) esters of 2-lysophosphatidylcholine (PC). HOHA-PC spontaneously releases a membrane-permeant HOHA lactone that modifies primary amino groups of proteins and ethanolamine phospholipids to produce 2-(ω-carboxyethyl)pyrrole (CEP) derivatives. CEPs have significant pathological relevance to age-related macular degeneration (AMD) including activation of CEP-specific T-cells leading to inflammatory M1 polarization of macrophages in the retina involved in "dry AMD" and TLR2-dependent induction of angiogenesis that characterizes "wet AMD". RPE cells accumulate DHA from shed rod photoreceptor outer segments through phagocytosis and from plasma lipoproteins secreted by the liver through active uptake from the choriocapillaris. As a cell model of light-induced oxidative damage of DHA phospholipids in RPE cells, ARPE-19 cells were supplemented with DHA, with or without the lipofuscin fluorophore A2E. In this model, light exposure, in the absence of A2E, promoted the generation HOHA lactone-glutathione (GSH) adducts, depletion of intracellular GSH and a competing generation of CEPs. While DHA-rich RPE cells exhibit an inherent proclivity toward light-induced oxidative damage, photosensitization by A2E nearly doubled the amount of lipid oxidation and expanded the spectral range of photosensitivity to longer wavelengths. Exposure of ARPE-19 cells to 1 µM HOHA lactone for 24 h induced massive (50%) loss of lysosomal membrane integrity and caused loss of mitochondrial membrane potential. Using senescence-associated ß-galactosidase (SA ß-gal) staining that detects lysosomal ß-galactosidase, we determined that exposure to HOHA lactone induces senescence in ARPE-19 cells. The present study shows that products of light-induced oxidative damage of DHA phospholipids in the absence of A2E can lead to RPE cell dysfunction. Therefore, their toxicity may be especially important in the early stages of AMD before RPE cells accumulate lipofuscin fluorophores.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Luz/efeitos adversos , Degeneração Macular/metabolismo , Estresse Oxidativo/efeitos da radiação , Epitélio Pigmentado da Retina/metabolismo , Células Cultivadas , Humanos , Peroxidação de Lipídeos , Lisossomos/metabolismo , Lisossomos/efeitos da radiação , Degeneração Macular/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos da radiação , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos
3.
Molecules ; 20(3): 4071-87, 2015 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-25749678

RESUMO

A series of novel aromatic carboxylic acid amides were synthesized and tested for their activities against six phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to good activity. Among them N-(2-(1H-indazol-1-yl)phenyl)-2-(trifluoromethyl)benzamide (3c) exhibited the highest antifungal activity against Pythium aphanidermatum (EC50 = 16.75 µg/mL) and Rhizoctonia solani (EC50 = 19.19 µg/mL), compared to the reference compound boscalid with EC50 values of 10.68 and 14.47 µg/mL, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed to develop a three-dimensional quantitative structure-activity relationship model for the activity of the compounds. In the molecular docking, a fluorine atom and the carbonyl oxygen atom of 3c formed hydrogen bonds toward the hydroxyl hydrogens of TYR58 and TRP173.


Assuntos
Amidas/química , Antifúngicos/síntese química , Antifúngicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Indazóis/síntese química , Indazóis/farmacologia , Micélio/efeitos dos fármacos , Pythium/efeitos dos fármacos , Rhizoctonia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Modelos Moleculares , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Pythium/crescimento & desenvolvimento , Relação Quantitativa Estrutura-Atividade , Rhizoctonia/crescimento & desenvolvimento
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