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.
Highlights
Invasive fungal infections are an increasing problem worldwide, contributing to 1.6 million deaths annually (Almeida et al, 2019; Bongomin et al, 2017; Brown et al, 2012)
We previously demonstrated that overlap2 method (O2M) identifies genes whose knockout mutants, termed synergy prediction mutants, exhibit phenotypes that are indicative of synergistic interactions between small molecules (Brown et al, 2014; Wambaugh et al, 2017)
O2M identifies synergy prediction mutants by using a chemical-genetics dataset, in which a library of knockout mutants is grown in the presence of >100 small molecules
Summary
Invasive fungal infections are an increasing problem worldwide, contributing to 1.6 million deaths annually (Almeida et al, 2019; Bongomin et al, 2017; Brown et al, 2012). These problematic infections are difficult to treat for many reasons. The paucity and toxicity of antifungal drugs, and the already immunocompromised state of many patients result in mortality rates of up to 90% (Brown et al, 2012; Pianalto and Alspaugh, 2016; Scorzoni et al, 2017). The need for more and better antifungal therapeutics is evident
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