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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 (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
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“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
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“In this context, studies on the interaction between azoles and statins have gained renewed attention.10,11,27,32,37”
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Combination Antifungal Therapy: The New Frontier
Vázquez, J. A. (2007) · Future Microbiology · doi:10.2217/17460913.2.2.115 · Cited by 21
“In an unconventional in vitro study, Chamilos and colleagues evaluated the use of lovastatin in combination with voriconazole against different Zygomycetes [118].”
BackgroundLukács, G., Papp, T., Somogyvári, F., Csernetics, Á., Nyilasi, I., & Vágvölgyi, C. (2009) · Antonie van Leeuwenhoek · doi:10.1007/s10482-008-9287-2 · Cited by 19
“In previous studies, the tested Zygomycetes showed variable susceptibilities against the different statins (Lukács et al. 2004; Chamilos et al. 2006; Galgóczy et al. 2007), although effects of simvastatin and fluvastatin on Mucor have not been examined until the present study.”
BackgroundNovel avenues for identification of new antifungal drugs and current challenges
Jampílek, J. (2022) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2022.2097659 · Cited by 20
Ebrahimi, A., Hemati, M., Shabanpour, Z., Dehkordi, S. H., Bahadoran, S., Lotalian, S., & Khoibani, S. (2015) · Jundishapur Journal of Microbiology · doi:10.5812/jjm.16058 · Cited by 19
Haidar, G., & Singh, N. (2018) · Transplantation · doi:10.1097/tp.0000000000002353 · Cited by 19
Immunotherapy of infections caused by rare filamentous fungi
Katragkou, A., & Roilides, E. (2011) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2011.03689.x · Cited by 16
“In fact, statins induce apoptosis-like cell death in Mucor racemosus [54], and in vitro data have shown that lovastatin has activity against a range of zygomycetes and a synergistic effect with voriconazole [55].”
BackgroundSarvestani, A. S., Pishdad, G. R., & Bolandparvaz, S. (2013) · PubMed Central · Cited by 16
In vitro interaction between suramin and fluvastatin against clinically important Zygomycetes
Galgóczy, L., Papp, T., & Vágvölgyi, C. (2009) · Mycoses · doi:10.1111/j.1439-0507.2008.01634.x · Cited by 14
An overview on the therapeutic potential and anticancer mechanism of Monacolin K / Lovastatin
Monu, M., Sehrawat, K. D., Singh, A. P., Chaudhary, G., Bamal, D., & Sehrawat, A. R. (2022) · Pharmacological Research - Modern Chinese Medicine · doi:10.1016/j.prmcm.2022.100187 · Cited by 14
Ghalwash, D. M., Abou‐Bakr, A., Hussein, R. R., & El‐Gawish, A. A. (2024) · The Egyptian Journal of Otolaryngology · doi:10.1186/s43163-024-00614-4 · Cited by 14
“There are several purported risk factors for mucor-mycosis, including type 1, type 2, and secondary DM [33].”
BackgroundCase–control study of statin prevention of mould infections
Thompson, J. N., Huycke, M. M., Greenfield, R. A., Kurdgelashvili, G., & Gentry, C. A. (2011) · Mycoses · doi:10.1111/j.1439-0507.2010.01957.x · Cited by 14
Effect of HMG‐CoA reductase inhibitors on antimicrobial susceptibilities for Gram‐Negative rods
Farmer, A. R., Murray, C. K., Mende, K., Akers, K. S., Zera, W. C., Beckius, M. L., & Yun, H. C. (2012) · Journal of Basic Microbiology · doi:10.1002/jobm.201100614 · Cited by 14
Is there a role for statins in fungal infections?
Bergman, P. W., & Björkhem-Bergman, L. (2013) · Expert Review of Anti-infective Therapy · doi:10.1586/14787210.2014.856755 · Cited by 12
Antifungal Targets, Mechanisms of Action, and Resistance in Candida albicans
Akins, R. A., & Sobel, J. D. (2009) · Humana Press eBooks · doi:10.1007/978-1-59745-180-2_29 · Cited by 12
L’activité antifongique des statines
Lefebvre, M., ALshawa, K., & Dupont, B. (2010) · Journal de Mycologie Médicale · doi:10.1016/j.mycmed.2010.05.007 · Cited by 12
Quindós, G., Carrillo‐Muñoz, A. J., Eraso, E., Cantón, E., & Pemán, J. (2007) · Revista Iberoamericana de Micología · doi:10.1016/s1130-1406(07)70043-8 · Cited by 11
“Otro campo de estudio interesante es la combinación terapéutica de antifúngicos y otros fármacos, como determinados anestésicos locales, como lidocaina y bupivacaina [129], o con las estatinas, como lovastatina, con la que se ha descrito una acción sinérgica in vitro de voriconazol combinado con lovastatina contra ais…”
BackgroundSpader, T. B., Ramírez-Castrillón, M., Valente, P., Alves, S. H., & Severo, L. C. (2019) · Mycopathologia · doi:10.1007/s11046-019-0317-6 · Cited by 10
Focusing COVID-19-associated mucormycosis: a major threat to immunocompromised COVID-19
Sharma, N., Wani, S. N., Behl, T., Singh, S., Zahoor, I., Sehgal, A., Bhatia, S., Al‐Harrasi, A., Aleya, L., & BUNGAU, S. G. (2022) · Environmental Science and Pollution Research · doi:10.1007/s11356-022-24032-2 · Cited by 11
Fungal Necrotizing Skin and Soft Tissue Infections
Bartram, L., & Aaron, J. G. (2019) · Current Fungal Infection Reports · doi:10.1007/s12281-019-00355-5 · Cited by 9
Cortez, J., Gomes, B. C., Speidel, A., Peixoto, C., Selicka, E., Valente, C., Figueiredo, P., & Vieira, A. (2013) · Medical Mycology Case Reports · doi:10.1016/j.mmcr.2013.02.008 · Cited by 8
Programmed cell death in human pathogenic fungi – a possible therapeutic target
Leiter, É., Csernoch, L. J., & Pócsi, I. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1541087 · Cited by 7
“formation of the MRas1/p20 protein complex [23].”
Experimental Models to Study the Pathogenesis and Treatment of Mucormycosis
Ben‐Ami, R. (2024) · Journal of Fungi · doi:10.3390/jof10010085 · Cited by 6
“Animal models offer opportunities to extend in vitro observations and establish in vivo drug activity, before proceeding to controlled clinical trials [17–27].”
BackgroundMethodInfluentialSingh, A., Pandey, S., Singh, S., & Kumar, N. (2015) · International Journal of Health & Allied Sciences · doi:10.4103/2278-344x.160890 · Cited by 6
“In addition to lipid‐lowering attributes, statins (lovastatin) have fungicidal activity against Glomeromycota and act synergistically with other antifungal agents, such as voriconazole.([18]) Granulocyte transfusions specially in patients with neutropenia improves the treatment outcomes against mucormycosis.”
BackgroundTakeshi, M., Yahata, Y., & Tsukune, Y. (2011) · Medical Mycology Journal · doi:10.3314/mmj.52.283 · Cited by 6
Eshkaleti, M. N., Kordbacheh, P., Hashemi, S. J., Falahati, M., Zaini, F., Mirhendi, H., Safara, M., & Hosseinpoor, L. (2019) · Iranian Journal of Public Health · doi:10.18502/ijph.v48i5.1812 · Cited by 6
“Statins in high concentrations are active against some clinically important fungi (27-29).”
BackgroundLatest Thoughts on Treating Pediatric Mucormycosis
Steinbach, W. J. (2020) · Journal of the Pediatric Infectious Diseases Society · doi:10.1093/jpids/piaa106 · Cited by 5
Ostroumova, O. S., & Efimova, S. S. (2023) · Antibiotics · doi:10.3390/antibiotics12121716 · Cited by 7
Combination Therapy for the Treatment of Mucormycosis: Examining the Evidence
Huang, A. M., Nagel, J. L., Crass, R. L., & Nguyen, C. T. (2015) · Current Fungal Infection Reports · doi:10.1007/s12281-015-0222-5 · Cited by 5
Yang, X., Huang, Q., Xu, J., Gao, Z., Jiang, X., Wu, Y., Ye, W., & Yue, L. (2022) · Journal of Applied Microbiology · doi:10.1111/jam.15792 · Cited by 4
“Statins treatment is able to reduce the intracellular sterol level in fungi and showed a synergistic effect with triazoles (Chamilos et al., 2006).”
BackgroundTopical statins as antifungals: a review
Khoury, D. M., Ghaoui, N., El Tayar, E., Dagher, R., El Hawa, M., Rubeiz, N., Abbas, O., & Kurban, M. (2024) · International Journal of Dermatology · doi:10.1111/ijd.17068 · Cited by 3
Inhibition of Siderophores in Blocking Fungal Infection
Bhatia, S., & Singh, S. (2021) · Fungal biology · doi:10.1007/978-3-030-53077-8_2 · Cited by 3
Metadata
- 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 › Infectious Diseases › 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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