A Systematic Screen Reveals a Diverse Collection of Medications That Induce Antifungal Resistance in Candida Species

Abstract

The increasing incidence of and high mortality rates associated with invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. In addition to microbiological resistance to existing antifungal drugs, the large number of unexplained treatment failures is a serious concern. Due to the extremely limited therapeutic options available, it is critical to identify and understand the various causes of treatment failure if patient outcomes are to improve. In this study, we examined one potential source of treatment failure: antagonistic drug interactions. Using a simple screen, we systematically identified currently approved medications that undermine the antifungal activity of three major antifungal drugs-fluconazole, caspofungin, and amphotericin B-on four prevalent human fungal pathogens-Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicalis. This revealed that a diverse collection of structurally distinct drugs exhibit antagonistic interactions with fluconazole. Several antagonistic agents selected for follow-up studies induce azole resistance through a mechanism that depends on Tac1p/Pdr1p zinc-cluster transcription factors, which activate the expression of drug efflux pumps belonging to the ABC-type transporter family. Few antagonistic interactions were identified with caspofungin or amphotericin B, possibly reflecting their cell surface mode of action that should not be affected by drug efflux mechanisms. Given that patients at greatest risk of IFIs usually receive a multitude of drugs to treat various underlying conditions, these studies suggest that chemically inducible azole resistance may be much more common and important than previously realized.

The atypical antipsychotic aripiprazole alters the outcome of disseminatedCandida albicansinfections

“…CDR2 encodes a multi-drug efflux pump of the ATP-binding cassette superfamily and has an established role in facilitating genetically encoded azole resistance in C. albicans (26), while RTA3 encodes a phospholipid translocase also previously shown to affect azole-tolerance (27). These results are consistent with our previous data showing that the azole-antagonistic activity of aripiprazole is dependent upon the Tac1p transcription factor, which activates the transcription of CDR2 (16). Several additional transcripts known to be either induced by Tac1p, or following exposure to fluphenazine (a known activator of Tac1p) (28), were identified as being elevated by one or more of the three drugs.…”

“…This specific study assessed the impact of several drugs we previously found to oppose the antifungal activity of the azole class of antifungals, upon C. albicans (16). Genetically encoded azole-resistance in C. albicans is often associated with point mutations in one or more key transcription factors that regulate the expression of the target enzyme Erg11p, or of multi-drug efflux pumps.…”

“…As such, it is likely that the physiology of fungi residing within the human body as part of the endogenous microbiota, or as invasive pathogens may be inadvertently targeted by the medications consumed by their host. Previously, we determined that a variety of drugs approved for human use can oppose the antifungal activity of fluconazole upon C. albicans (16) in vitro . Seven of these antagonists were selected for further evaluation in this study (Table 1), including the atypical antipsychotic aripiprazole.…”

Antifungal Activity of the Natural Coumarin Scopoletin Against Planktonic Cells and Biofilms From a Multidrug-Resistant Candida tropicalis Strain

“…Invasive fungal infections produced by Candida spp. persist as the primary hospital-acquired bloodstream infections and are associated with high morbidity and mortality, especially in intensive care units (Kauffman, 2015;McCarthy and Walsh, 2017;Butts et al, 2019). While Candida albicans remains as the most frequent fungal species isolated from candidemic patients, other Candida species are often identified in clinical isolates (Reviewed in Guinea, 2014).…”

Data vignettes for the application of response surface models in drug combination analysis

“…It also contains a pre-processed tabular data file (“Data06_Raw02_ButtsEtAl_Antifungal.txt”) containing the assay results for penbutolol and fluconazole in an antifungal screen reported by Butts et al. [9] . The R script file “Data06_Script01_AtypicalSurfaces.R” extracts the data from these two files, fits them with a traditional BRAID surface, as well as a transformed oppositional or protective BRAID surface, and reports all fit results.…”