Bisphosphonates synergistically enhance the antifungal activity of azoles in dermatophytes and other pathogenic molds.

Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101674533 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2379-5042 (Electronic) Linking ISSN: 23795042 NLM ISO Abbreviation: mSphere Subsets: MEDLINE

Original Publication: Washington, DC : American Society for Microbiology, [2015]-

Antifungal Agents*/pharmacology ; Drug Synergism* ; Arthrodermataceae*/drug effects ; Microbial Sensitivity Tests* ; Diphosphonates*/pharmacology; Humans ; Azoles/pharmacology ; Biofilms/drug effects ; Drug Resistance, Fungal ; Fungi/drug effects

Superficial infections of the skin, hair, and nails by fungal dermatophytes are the most prevalent of human mycoses, and many infections are refractory to treatment. As current treatment options are limited, recent research has explored drug synergy with azoles for dermatophytoses. Bisphosphonates, which are approved to treat osteoporosis, can synergistically enhance the activity of azoles in diverse yeast pathogens but their activity has not been explored in dermatophytes or other molds. Market bisphosphonates risedronate, alendronate, and zoledronate (ZOL) were evaluated for antifungal efficacy and synergy with three azole antifungals: fluconazole (FLC), itraconazole (ITR), and ketoconazole (KET). ZOL was the most active bisphosphonate tested, displaying moderate activity against nine dermatophyte species (MIC range 64-256 µg/mL), and was synergistic with KET in eight of these species. ZOL was also able to synergistically improve the anti-biofilm activity of KET and combining KET and ZOL prevented the development of antifungal resistance. Rescue assays in Trichophyton rubrum revealed that the inhibitory effects of ZOL alone and in combination with KET were due to the inhibition of squalene synthesis. Fluorescence microscopy using membrane- and ROS-sensitive probes demonstrated that ZOL and KET:ZOL compromised membrane structure and induced oxidative stress. Antifungal activity and synergy between bisphosphonates and azoles were also observed in other clinically relevant molds, including species of Aspergillus and Mucor . These findings indicate that repurposing bisphosphonates as antifungals is a promising strategy for revitalising certain azoles as topical antifungals, and that this combination could be fast-tracked for investigation in clinical trials.
Importance: Fungal infections of the skin, hair, and nails, generally grouped together as "tineas" are the most prevalent infectious diseases globally. These infections, caused by fungal species known as dermatophytes, are generally superficial, but can in some cases become aggressive. They are also notoriously difficult to resolve, with few effective treatments and rising levels of drug resistance. Here, we report a potential new treatment that combines azole antifungals with bisphosphonates. Bisphosphonates are approved for the treatment of low bone density diseases, and in fungi they inhibit the biosynthesis of the cell membrane, which is also the target of azoles. Combinations were synergistic across the dermatophyte species and prevented the development of resistance. We extended the study to molds that cause invasive disease, finding synergy in some problematic species. We suggest bisphosphonates could be repurposed as synergents for tinea treatment, and that this combination could be fast-tracked for use in clinical therapy.
Competing Interests: The authors declare no conflict of interest.

J Med Chem. 2017 Mar 23;60(6):2326-2343. (PMID: 28121436)
Nat Protoc. 2008;3(9):1494-500. (PMID: 18772877)
Biofouling. 2014;30(6):719-27. (PMID: 24856309)
Methods Mol Biol. 2017;1508:17-65. (PMID: 27837497)
Mycoses. 2011 Nov;54(6):e666-78. (PMID: 21672045)
J Am Podiatr Med Assoc. 2016 Jan-Feb;106(1):79-86. (PMID: 26895366)
Mycoses. 2008 Sep;51 Suppl 4:2-15. (PMID: 18783559)
J Cutan Med Surg. 2015 Jul-Aug;19(4):352-7. (PMID: 25775613)
Fungal Genet Biol. 2019 Nov;132:103255. (PMID: 31330295)
Med Mycol. 2008 Jun;46(4):303-13. (PMID: 18415837)
Nat Rev Drug Discov. 2017 Sep;16(9):603-616. (PMID: 28496146)
ACS Med Chem Lett. 2013 Apr 11;4(4):423-427. (PMID: 23610597)
Br J Dermatol. 2001 Oct;145 Suppl 60:15-9. (PMID: 11777260)
J Infect. 2014 May;68(5):478-93. (PMID: 24378282)
Int J Dermatol. 2000 Apr;39(4):302-4. (PMID: 10809984)
Pathogens. 2021 Feb 11;10(2):. (PMID: 33670403)
J Am Acad Dermatol. 2006 Sep;55(3):490-500. (PMID: 16908356)
Mycopathologia. 2017 Feb;182(1-2):5-31. (PMID: 27783317)
Pharmaceuticals (Basel). 2022 Apr 14;15(4):. (PMID: 35455479)
Mayo Clin Proc. 2008 Sep;83(9):1032-45. (PMID: 18775204)
Mycopathologia. 2017 Feb;182(1-2):127-141. (PMID: 27502503)
Drug Saf. 1996 Mar;14(3):158-70. (PMID: 8934578)
Cold Spring Harb Perspect Med. 2014 Aug 01;4(8):. (PMID: 25085959)
Microbiol Spectr. 2024 Jun 4;12(6):e0012124. (PMID: 38695556)
J Antimicrob Chemother. 2003 Jul;52(1):1. (PMID: 12805255)
Antimicrob Agents Chemother. 2021 Jan 20;65(2):. (PMID: 33139289)
Calcif Tissue Int. 2011 Aug;89(2):91-104. (PMID: 21637997)
J Family Med Prim Care. 2019 Aug 28;8(8):2577-2581. (PMID: 31548935)
J Eur Acad Dermatol Venereol. 2021 Jul;35(7):1582-1586. (PMID: 33768571)
Mycopathologia. 2020 Apr;185(2):233-243. (PMID: 32108288)
J Fungi (Basel). 2021 Sep 05;7(9):. (PMID: 34575765)
Antimicrob Agents Chemother. 2015 Dec;59(12):7530-9. (PMID: 26392508)
Antimicrob Agents Chemother. 2005 Mar;49(3):945-51. (PMID: 15728887)
J Fungi (Basel). 2023 Feb 09;9(2):. (PMID: 36836342)
Expert Opin Pharmacother. 2014 Aug;15(12):1707-13. (PMID: 24991691)

University of Sydney MBI Seed Funding Grant

Keywords: Trichophyton; antifungal agents; antifungal therapy; azole; bisphosphonate; dermatophytes; drug synergy; ketoconazole; zolendronate

0 (Antifungal Agents)
0 (Diphosphonates)
0 (Azoles)

Date Created: 20240605 Date Completed: 20240625 Latest Revision: 20240821

20240821

PMC11332346

10.1128/msphere.00248-24

38837382