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Abstract
The large increase in the population of immunosuppressed patients, coupled with the limited efficacy of existing antifungals and rising resistance toward them, have dramatically highlighted the need to develop novel drugs for the treatment of invasive fungal infections. An attractive possibility is the identification of possible drug targets within essential fungal metabolic pathways not shared with humans. Here, we review the vitamin biosynthetic pathways (vitamins A–E, K) as candidates for the development of antifungals. We present a set of ranking criteria that identify the vitamin B2 (riboflavin), B5 (pantothenic acid), and B9 (folate) biosynthesis pathways as being particularly rich in new antifungal targets. We propose that recent scientific advances in the fields of drug design and fungal genomics have developed sufficiently to merit a renewed look at these pathways as promising sources for the development of novel classes of antifungals.
Highlights
The number of life-threatening fungal infections has risen dramatically over the last twenty years
Recent estimates have identified a global burden of almost two million patients with systemic and invasive fungal infections, including ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~220,000 cases of cryptococcal meningitis, and ~100,000 cases of disseminated histoplasmosis [1,2]
This review focuses exclusively on the essential vitamin biosynthetic pathways (A, B1–12, C, D, E, and K) and their suitability as antifungal drug targets
Summary
The number of life-threatening fungal infections has risen dramatically over the last twenty years. During the last two decades, extensive molecular studies have helped identify several fungal-specific drug targets shared by the most important human pathogenic fungi, Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, and not found in higher eukaryotes including humans [7,8,9,10]. Inhibition of riboflavin biosynthesis strongly (>80%) reduces the production of siderophores [27], delivering an unexpected advantage by inhibiting fungal iron acquisition and growth during infection Despite their potential, to date there are few antifungals targeting the vitamin biosynthetic pathways. It lacks a druggable target, while vitamins E and K are only synthesized by plants and not fungi
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