The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections
Open accessAbstract
Therapeutic treatment for systemic mycoses is severely hampered by the extremely limited number of antifungals. The difficulty of treatment of fungal infections in the central nervous system is further compounded by the poor central nervous system (CNS) penetration of most antifungals due to the blood-brain barrier. Only a few fungistatic azole drugs, such as fluconazole, show reasonable CNS penetration. Here we demonstrate that sertraline (Zoloft), the most frequently prescribed antidepressant, displays potent antifungal activity against Cryptococcus neoformans , the major causative agent of fungal meningitis. In in vitro assays, this neurotropic drug is fungicidal to all natural Cryptococcus isolates tested at clinically relevant concentrations. Furthermore, sertraline interacts synergistically or additively with fluconazole against Cryptococcus . Importantly, consistent with our in vitro observations, sertraline used alone reduces the brain fungal burden at an efficacy comparable to that of fluconazole in a murine model of systemic cryptococcosis. It works synergistically with fluconazole in reducing the fungal burden in brain, kidney, and spleen. In contrast to its potency against Cryptococcus , sertraline is less effective against strains of Candida species and its interactions with fluconazole against Candida strains are often antagonistic. Therefore, our data suggest the unique application of sertraline against cryptococcosis. To understand the antifungal mechanisms of sertraline, we screened a whole-genome deletion collection of Saccharomyces cerevisiae for altered sertraline susceptibility. Gene ontology analyses of selected mutations suggest that sertraline perturbs translation. In vitro translation assays using fungal cell extracts show that sertraline inhibits protein synthesis. Taken together, our findings indicate the potential of adopting this antidepressant in treating cryptococcal meningitis.
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Several psychotherapeutic agents such as fluoxetine, fluphenazine, or sertraline can enhance FLC activity against fungal species.
“In addition, several psychotherapeutic agents such as fluoxetine, fluphenazine (FNZ), or sertraline can enhance FLC activity against fungal species 14,15 .”
From Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia (2018) · cites this paper as [15]
The Results (p. 4) report that sertraline increases fluconazole activity against the tested Cryptococcus strains. The paper does not establish the same effect for fluoxetine or fluphenazine, and the Results (p. 5) report that sertraline often antagonizes fluconazole against Candida strains. The claim therefore overgeneralizes both the agents and the fungal species. (LLM, conf=0.89)
Experimental — accuracy not yet measuredSertraline was initially demonstrated to potentiate the action of azoles against cryptococcal microbes.
“Sertraline was initially demonstrated to be able to potentiate the action of azoles against cryptococcal microbes [60]; later, it was tested in a Phase II study [94] and a follow-up Phase III study in HIV patients infected by this fungus, but with no convincing results [95].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [60]
Sertraline acts synergistically with fluconazole in a mouse model of systemic cryptococcosis, reducing the fungal burden.
“Originally developed as an antidepressant, sertraline acts synergistically with fluconazole in a mouse model of systemic cryptococcosis, reducing the fungal burden105.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [105]
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- Authors
- Zhai, B., Wu, C., Wang, L., Sachs, M. S., & Lin, X.
- Affiliations
- Texas A&M University (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2012-07
- Volume
- 56
- Issue
- 7
- Pages
- 3758-3766
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3393448
- OpenAlex
- W2172160469
- Cited by
- 205
- References
- 44
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 19 · 2023: 18 · 2022: 18 · 2021: 13 · 2020: 21 · 2019: 24 · 2018: 12 · 2017: 15 · 2016: 18 · 2015: 9 · 2014: 6 · 2013: 5 · 2012: 2
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OakTrust (Texas A&M University Libraries) (submittedVersion)
- Funders
- American Heart Association
- Johns Hopkins University
- National Institute of General Medical Sciences (R01GM47498, R01GM047498)
- National Institute of Allergy and Infectious Diseases (R01AI097599)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- sertraline, Cryptococcus neoformans, cryptococcosis, cryptococcal meningitis, antifungal activity, fluconazole, drug synergy, drug repurposing, antidepressants, Candida, protein synthesis inhibition, blood-brain barrier, systemic fungal infection
- MeSH terms
- Animals, Antidepressive Agents, Cryptococcosis, Cryptococcus neoformans, Female, Microbial Sensitivity Tests, Saccharomyces cerevisiae, Fluconazole, Sertraline, Mice
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