{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:21:32Z","timestamp":1785424892792,"version":"3.56.0"},"reference-count":53,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100011890","name":"Marie Bashir Institute, University of Sydney","doi-asserted-by":"publisher","award":["Seed Funding"],"award-info":[{"award-number":["Seed Funding"]}],"id":[{"id":"10.13039\/501100011890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,2,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Farnesyl pyrophosphate synthetase (FPPS) is a critical enzyme for squalene biosynthesis. In fungi, squalene is the primary substrate of the ergosterol biosynthesis pathway, which is the target of azole antifungals. Bisphosphonate-based FPPS inhibitors like zoledronate (ZOL) have limited antifungal activity alone but are highly synergistic with azoles against a broad array of human fungal pathogens. Various bisphosphonate drugs are available and are FDA-approved for bone resorption disorders, but their use as antifungal therapeutics is limited by their poor systemic bioavailability. To overcome this, we synthesized a suite of different FPPS inhibitors that incorporated alkyl tails of various lengths to improve solubility, cell penetration, and FPPS inhibition. A derivative of ZOL with an attached 10-carbon alkyl tail (here named 10-ZOL) was also produced. Most of the inhibitors demonstrated limited efficacy and had inconsistent interactions with azole antifungals; however, 10-ZOL had dramatically improved antifungal activity\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      across a broad spectrum of pathogens (minimum inhibitory concentration range = 0.5\u20138 \u00b5g\/mL),\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      efficacy in an invertebrate model of infection, and a low level of toxicity in mammalian cells (IC\n                      <jats:sub>50<\/jats:sub>\n                      = 35.77 \u00b5g\/mL). Rescue with exogenous squalene revealed that 10-ZOL, like ZOL, acts by inhibiting squalene synthesis, resulting in changes to the membrane lipid environment. Cell-based assays showed that these lipid changes compromised plasma membrane structure and integrity and caused an accumulation of toxic oxygen radicals. We conclude that 10-ZOL is a promising new therapeutic lead due to its broad spectrum of activity and synergistic interactions with azoles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      At least 1.6 million lives are lost every year to invasive fungal infections, and topical infections like candidiasis and dermatophytosis are extremely widespread. The current arsenal of antifungal drugs is severely limited; most are either toxic to humans or have a narrow spectrum of activity, and antifungal resistance is an emerging concern. These problems demand new druggable targets with approaches that can mitigate resistance. Here, we build on a body of work that found the disruption of squalene synthesis by bisphosphonates to be a promising approach for synergistically enhancing azole antifungals and preventing the development of resistance. We find an alkylated derivative of the bisphosphonate zoledronate, termed 10-ZOL, to be highly antifungal\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      against an extremely diverse spectrum of fungal pathogens, with minimal toxicity to mammalian cells.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.03199-25","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T14:00:34Z","timestamp":1766412034000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Alkylation-based optimization of antifungal FPPS inhibitors yields a potent, broad-spectrum lipophilic zoledronate derivative"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4927-0071","authenticated-orcid":false,"given":"Aidan","family":"Kane","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0384j8v12","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life and Environmental Sciences, The University of Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felcia","family":"Lai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0384j8v12","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmacy, The University of Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna G.","family":"Rothwell","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0384j8v12","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life and Environmental Sciences, The University of 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