The Anti-Fungal Activity of Nitropropenyl Benzodioxole (NPBD), a Redox-Thiol Oxidant and Tyrosine Phosphatase Inhibitor

Abstract

Phylogenetically diverse fungal species are an increasing cause of severe disease and mortality. Identification of new targets and development of new fungicidal drugs are required to augment the effectiveness of current chemotherapy and counter increasing resistance in pathogens. Nitroalkenyl benzene derivatives are thiol oxidants and inhibitors of cysteine-based molecules, which show broad biological activity against microorganisms. Nitropropenyl benzodioxole (NPBD), one of the most active antimicrobial derivatives, shows high activity in MIC assays for phylogenetically diverse saprophytic, commensal and parasitic fungi. NPBD was fungicidal to all species except the dermatophytic fungi, with an activity profile comparable to that of Amphotericin B and Miconazole. NPBD showed differing patterns of dynamic kill rates under different growth conditions for Candida albicans and Aspergillus fumigatus and was rapidly fungicidal for non-replicating vegetative forms and microconidia. It did not induce resistant or drug tolerant strains in major pathogens on long term exposure. A literature review highlights the complexity and interactivity of fungal tyrosine phosphate and redox signaling pathways, their differing metabolic effects in fungal species and identifies some targets for inhibition. A comparison of the metabolic activities of Amphotericin B, Miconazole and NPBD highlights the multiple cellular functions of these agents and the complementarity of many mechanisms. The activity profile of NPBD illustrates the functional diversity of fungal tyrosine phosphatases and thiol-based redox active molecules and contributes to the validation of tyrosine phosphatases and redox thiol molecules as related and complementary selective targets for antimicrobial drug development. NPBD is a selective antifungal agent with low oral toxicity which would be suitable for local treatment of skin and mucosal infections.