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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.<\/jats:p>","DOI":"10.7554\/elife.54160","type":"journal-article","created":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T20:00:58Z","timestamp":1588622458000},"source":"Crossref","is-referenced-by-count":65,"title":["Synergistic and antagonistic drug interactions in the treatment of systemic fungal infections"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6663-2017","authenticated-orcid":true,"given":"Morgan A","family":"Wambaugh","sequence":"first","affiliation":[{"name":"Division of Microbiology and Immunology, Pathology Department, University of Utah School of Medicine, Salt Lake City, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven T","family":"Denham","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Pathology Department, University of Utah School of Medicine, Salt Lake City, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Ayala","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Pathology Department, University of Utah School of Medicine, Salt Lake City, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna","family":"Brammer","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Pathology Department, University of Utah School of Medicine, Salt Lake City, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miekan A","family":"Stonhill","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Pathology Department, University of Utah School of Medicine, Salt Lake City, United 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