Diffusion-mediated quantification of dose-dependent antifungal drug tolerance

Abstract

Antimicrobial resistance is a global health problem, with drug-resistant fungi posing major challenges for the treatment of immunocompromised patients. Antifungal tolerance is a recently discovered phenomenon whereby pathogenic fungi, including the multidrug-resistant pathogenic yeast Candidozyma auris (formerly Candida auris), grow slowly above minimum inhibitory drug concentrations. We combine physics-based spatiotemporal models with microbiology experiments to quantitatively investigate the emergence of tolerance to all three major classes of antifungal drugs in C. auris. Specifically, we combine Ficks second law solved using a finite difference method to simulate drug diffusion with data from experimental disk diffusion assays to determine the concentration ranges at which antifungal-tolerant colonies emerge. This biophysics study advances antimicrobial resistance research by providing a method to quantify antifungal tolerance and by demonstrating that antifungal tolerance is a strain-, drug-, and dose-dependent phenomenon in an emerging fungal pathogen.