Conventional antifungal treatments are lackluster against the increasing invasive fungal infections in immunocompromised patients. Treatments against Cryptococcus neoformans has a mortality rate between 30% to 80% depending on the resources available. Ciclopirox olamine (CPO), an N-hydroxypyridone (HPO), has been used in topical antifungal creams and was found to be effective against C. neoformans in vitro. We tested 10 synthetic HPOs to define a structure-activity relationship (SAR) and understand HPOs’ mechanism of action. These HPOs have variable minimal inhibitory concentration (MIC80) and cytotoxicity concentrations (CC50). Variable substitution at position 6 is supported with relatively low MICs maintained while substitutions at positions 4 and 5 lose the inhibition activity but increase the CC50. Additionally, CPO is synergistic with HPOs, and all HPOs are synergistic with iron chelators such as deferoxamine mesylate (DFO) and deferiprone (DFP). Also, HPOs are synergistic with some mitochondrial electron transport chain inhibitors; mainly, complex I, alternative oxidase, and complex IV inhibitors. HPOs show additive or indifferent effects with complex II and complex III inhibitors. The findings suggest that substitutions to CPO can increase efficacy and decrease toxicity, and HPOs potentially act through iron chelation at the active site of iron dependent enzymes. Malassezia spp., a genus of fungi that are lipid dependent, can cause infections in a wide range of warm-blooded animals. More than 30% of immunocompromised patients are affected by seborrheic dermatitis caused by Malassezia furfur. Moreover, canine dermatitis is caused by Malassezia pachydermatis. The difficulty to culture and lack of a screening protocol make drug screening in Malassezia spp. difficult to approach. Effective treatments for infections caused by either Malassezia species are reliant on drugs discovered more than 50 years ago. We identified a screening protocol that utilizes a lipid rich media and resazurin, a metabolic reporter, to obtain robust cell growth and to overcome the inconsistency of optical density reading (OD). We tested more than 60 compounds against both species and found that effective compounds are bulky and lipophilic. This could indicate that lipophilic antifungal compounds may be effective inhibitors of M. furfur and M. pachydermatis, however, additional screening is required for a definitive conclusion.
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