Frontiers in Cellular and Infection Microbiology (Feb 2023)

Antifungal activity of 6-substituted amiloride and hexamethylene amiloride (HMA) analogs

  • Kiem Vu,
  • Benjamin J. Buckley,
  • Benjamin J. Buckley,
  • Richard S. Bujaroski,
  • Richard S. Bujaroski,
  • Richard S. Bujaroski,
  • Eduardo Blumwald,
  • Michael J. Kelso,
  • Michael J. Kelso,
  • Angie Gelli

DOI
https://doi.org/10.3389/fcimb.2023.1101568
Journal volume & issue
Vol. 13

Abstract

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Fungal infections have become an increasing threat as a result of growing numbers of susceptible hosts and diminishing effectiveness of antifungal drugs due to multi-drug resistance. This reality underscores the need to develop novel drugs with unique mechanisms of action. We recently identified 5-(N,N-hexamethylene)amiloride (HMA), an inhibitor of human Na+/H+ exchanger isoform 1, as a promising scaffold for antifungal drug development. In this work, we carried out susceptibility testing of 45 6-substituted HMA and amiloride analogs against a panel of pathogenic fungi. A series of 6-(2-benzofuran)amiloride and HMA analogs that showed up to a 16-fold increase in activity against Cryptococcus neoformans were identified. Hits from these series showed broad-spectrum activity against both basidiomycete and ascomycete fungal pathogens, including multidrug-resistant clinical isolates.

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