Cited by 205Fungal Infections and StudiesAntifungal resistance and susceptibilityFungal Plant Pathogen Control

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The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections

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Zhai, Bing, Wu, Cheng, Wang, Linqi, Sachs, Matthew S., Lin, Xiaorong·2012·Antimicrobial Agents and Chemotherapy

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Abstract

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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Authors: Zhai, B., Wu, C., Wang, L., Sachs, M. S., & Lin, X.
Affiliations: Texas A&M University (US)
ORCID: Zhai, Bing
Wu, Cheng
Wang, Linqi
Sachs, Matthew S.
Lin, Xiaorong
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
DOI: 10.1128/aac.00212-12
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
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
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 › Infectious Diseases › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Agricultural and Biological Sciences › Plant Science › 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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The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections

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