Lovastatin Has Significant Activity against Zygomycetes and Interacts Synergistically with Voriconazole
Open accessAbstract
Zygomycetes are emerging opportunistic molds resistant to most conventional antifungals. We evaluated the in vitro activity of lovastatin (LOV), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, against seven clinical isolates of Zygomycetes by using standard microdilution methods in three different media, disk diffusion testing, and viability dye staining. To further study the in vivo efficacy of LOV against zygomycetes, we developed a Drosophila melanogaster model of zygomycosis. In different experiments, groups of Toll-deficient ( Tl ) flies fed LOV-containing food were subsequently injected with two representative Zygomycetes isolates ( Mucor and Rhizopus spp.). Finally, we examined the effects of LOV on voriconazole (VRC) activity against zygomycetes in vitro by checkerboard dilution, Epsilometer test-based methods, and bis-(1,3-dibutylbarbituric acid) trimethine oxonol staining and in vivo in Tl flies fed food containing LOV plus VRC and infected with zygomycetes. LOV exhibited significant, medium, and strain-independent fungicidal activity against all Zygomycetes isolates in vitro by all testing methods (MIC 50 , 48.0 μg/ml; 50% minimal fungicidal concentration, 56.0 μg/ml; 50% effective concentration, 29.4 μg/ml [6.6 to 38.9 μg/ml]). Tl flies fed LOV-containing food and infected with Mucor had a significantly better 6-day survival rate than did infected Tl flies fed regular food ( P = 0.0005). LOV displayed in vitro synergy with VRC against all Zygomycetes isolates (fractional inhibitory concentration index, 0.104 to 0.290) by all methods used. LOV also displayed synergy with VRC in the Drosophila model of zygomycosis ( P < 0.01). LOV is significantly active against zygomycetes and synergizes with triazoles inherently resistant to them, such as VRC. The clinical significance of these findings needs to be further explored.
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The obtained results are consistent with previous studies, which mentioned that there were synergistic interactions between statins and azole drugs against Candida spp. Saccharomyces cerevisiae and different filamentous fungi.
“The obtained results are consistent with previous studies, which mentioned that there were synergistic interactions between statins and azole drugs against Candida spp. Saccharomyces cerevisiae and different filamentous fungi (Lorenz and Parks 1990; Chamilos et al. 2006; Nyilasi et al. 2010).”
From In vitro study on the potential fungicidal effects of atorvastatin in combination with some azole drugs against multidrug resistant Candida albicans (2021) · cites this paper as Chamilos et al. 2006
The Discussion reports statin–azole synergy against Candida and finds lovastatin–voriconazole synergy against the filamentous Zygomycetes tested. The Abstract mentions statin activity against Saccharomyces cerevisiae, but does not say the statin and an azole acted synergistically against it. Page numbers are not supplied for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe synergism between ATO and azole drugs might be attributed to the combined action of these drugs in reducing fungal ergosterol synthesis, which led to increasing cell membrane permeability and increasing the penetration of azoles in the fungal cell.
“The synergism between ATO and azole drugs might be attributed to the combined action of these drugs in reducing fungal ergosterol synthesis, which led to increasing cell membrane permeability and increasing the penetration of azoles in the fungal cell (Chamilos et al. 2006; Nyilasi et al. 2010; Cabral et al. 2013; Lima et al. 2019).”
From In vitro study on the potential fungicidal effects of atorvastatin in combination with some azole drugs against multidrug resistant Candida albicans (2021) · cites this paper as Chamilos et al. 2006
The Discussion reports synergy between lovastatin and voriconazole and identifies sequential steps in ergosterol biosynthesis that statins and azoles inhibit. It calls that mechanism plausible rather than established. This paper tested lovastatin, not ATO, and does not report increased membrane permeability or azole penetration into fungal cells (Discussion; page not available). (LLM, conf=0.86)
Experimental — accuracy not yet measuredResearch into azole-statin interactions has attracted renewed interest.
“In this context, studies on the interaction between azoles and statins have gained renewed attention.10,11,27,32,37”
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- Authors
- Chamilos, G., Lewis, R. E., & Kontoyiannis, D. P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Kontoyiannis, Dimitrios P.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2006-01
- Volume
- 50
- Issue
- 1
- Pages
- 96-103
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC1346800
- OpenAlex
- W2121543756
- Cited by
- 121
- References
- 36
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 8 · 2021: 6 · 2020: 8 · 2019: 11 · 2018: 6 · 2017: 2 · 2016: 5 · 2015: 9 · 2014: 4 · 2013: 6 · 2012: 8
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- lovastatin, mucormycosis, Zygomycetes, voriconazole, drug synergy, statins, Mucor, Rhizopus, Drosophila model, antifungal activity, triazole resistance
- MeSH terms
- Animals, Antifungal Agents, Drug Synergism, Fungi, Lovastatin, Microbial Sensitivity Tests, Mycoses, Pyrimidines, Triazoles, Voriconazole
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