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

Kiem Vu; Benjamin J Buckley; Richard S Bujaroski; Eduardo Blumwald; Michael J Kelso; Angie Gelli

doi:10.3389/fcimb.2023.1101568

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

Front Cell Infect Microbiol. 2023 Feb 16:13:1101568. doi: 10.3389/fcimb.2023.1101568. eCollection 2023.

Authors

Kiem Vu¹, Benjamin J Buckley^{2

3}, Richard S Bujaroski^{2

3

4}, Eduardo Blumwald⁵, Michael J Kelso^{2

3}, Angie Gelli¹

Affiliations

¹ Department of Pharmacology, School of Medicine, University of California, Genome and Biomedical Sciences Facility, Davis, CA, United States.
² Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia.
³ Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
⁴ Monash Institute of Pharmaceutical Science (ATMCF), Monash University, Parkville, VIC, Australia.
⁵ Department of Plant Sciences, PRB Building, University of California, Davis, CA, Australia.

Abstract

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.

Keywords: Candida spp.; Cryptococcus neoformans; HMA; MFC; MIC; amiloride; analogs; antifungal activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amiloride / pharmacology
Antifungal Agents / pharmacology
Cryptococcus neoformans*
Fungi
Humans
Microbial Sensitivity Tests
Mycoses* / drug therapy

Substances

5-(N,N-hexamethylene)amiloride
Amiloride
Antifungal Agents

Grants and funding

The study was supported by the Will W. Lester Endowment of the University of California awarded to EB. MK was supported by Australian National Health and Medical Research Council (NHMRC) Project Grant (APP1100432). BB acknowledges salary support from the Illawarra Cancer Careers.