Synergistic and antagonistic drug interactions in the treatment of systemic fungal infections
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Abstract
Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments. The azole class antifungal, fluconazole, is widely available and has multi-species activity but only inhibits growth instead of killing fungal cells, necessitating long treatments. To improve treatment, we used our novel high-throughput method, the overlap2 method (O2M) to identify drugs that interact with fluconazole, either increasing or decreasing efficacy. We identified 40 molecules that act synergistically (amplify activity) and 19 molecules that act antagonistically (decrease efficacy) when combined with fluconazole. We found that critical frontline beta-lactam antibiotics antagonize fluconazole activity. A promising fluconazole-synergizing anticholinergic drug, dicyclomine, increases fungal cell permeability and inhibits nutrient intake when combined with fluconazole. In vivo, this combination doubled the time-to-endpoint of mice with Cryptococcus neoformans meningitis. Thus, our ability to rapidly identify synergistic and antagonistic drug interactions can potentially alter the patient outcomes.
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The overlap2 method applied to a compound library enriched for FDA-approved compounds against C. neoformans predicted that the anticholinergic drug dicyclomine HCl with fluconazole would serve as a potent anti-cryptococcal combination therapy.
“For example, the overlap2 method was applied to a compound library enriched for FDA-approved compounds against C. neoformans116–119 and successfully predicted that the anticholinergic drug dicyclomine HCl with fluconazole would serve as a potent anti-cryptococcal combination therapy.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [119]
The combination of dicyclomine HCl and fluconazole displayed enhanced efficacy in a mouse model of cryptococcal meningitis.
“Indeed, the combination of these drugs displayed enhanced efficacy in a mouse model of cryptococcal meningitis119.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [119]
A high-throughput approach, termed the overlap2 method, has been developed to predict synergistic and antagonistic drug pairs using at least one known synergistic drug pair and chemical-genetic data sets.
“A high-throughput approach has been developed to predict synergistic and antagonistic drug pairs using at least one known synergistic drug pair and chemical–genetic data sets118,119.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [119]
Several β-lactam antibiotics were identified as antagonistic with fluconazole in C. neoformans.
“Several β-lactam antibiotics were identified as antagonistic with fluconazole in C. neoformans, an important consideration given that susceptible patient populations often have comorbidities119.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [119]
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- Authors
- Wambaugh, M. A., Denham, S. T., Ayala, M., Brammer, B., Stonhill, M. A., & Brown, J. C.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Brown, Jessica CS
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-05-05
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7200157
- OpenAlex
- W3023583617
- Cited by
- 65
- References
- 100
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 12 · 2023: 15 · 2022: 12 · 2021: 6 · 2020: 4
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01AI137331, T32AI055434)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- drug interactions, fluconazole, invasive fungal infections, combination antifungal therapy, synergistic effect, antagonism, beta-lactam antibiotics, dicyclomine, anticholinergic agents, high-throughput drug screening
- MeSH terms
- Animals, Antifungal Agents, Cryptococcosis, Cryptococcus neoformans, Drug Antagonism, Drug Evaluation, Preclinical, Drug Synergism, Female, Humans, Mycoses, Structure-Activity Relationship, Fluconazole, Meningitis, Cryptococcal, Mice, High-Throughput Screening Assays
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