The importance of antimicrobial resistance in medical mycology

Abstract

Prior to the SARS-CoV-2 pandemic, antibiotic resistance was listed as the major global health care priority. Some analyses, including the O'Neill report, have predicted that deaths due to drug-resistant bacterial infections may eclipse the total number of cancer deaths by 2050. Although fungal infections remain in the shadow of public awareness, total attributable annual deaths are similar to, or exceeds, global mortalities due to malaria, tuberculosis or HIV. The impact of fungal infections has been exacerbated by the steady rise of antifungal drug resistant strains and species which reflects the widespread use of antifungals for prophylaxis and therapy, and in the case of azole resistance in Aspergillus, has been linked to the widespread agricultural use of antifungals. This review, based on a workshop hosted by the Medical Research Council and the University of Exeter, illuminates the problem of antifungal resistance and suggests how this growing threat might be mitigated.

Fig. 1. Overview of antifungal drug responses.

Antifungal drug resistance (left side) is detected as elevated MIC due to direct effects on drug (orange circle) or drug target (blue star), via reduced binding affinity of the target for the drug, increased levels of the target that dilute the drug effect, or by reducing the intracellular drug concentration via drug efflux or blocked drug uptake. Antifungal drug tolerance (right side) is a physiological response to drug stress involving pathways that buffer the stress, such that some cells are able to grow, albeit slowly, in the presence of drug concentrations that are inhibitory to other cells in the population. This involves physiological shifts in: the cell wall or membrane integrity pathways (including pathways regulated by Hsp90, calcineurin, and the Crz1 transcription factor, and pathways affecting membrane lipid composition); protein translation machinery including the TOR pathway; and modifications of mitochondrial function. Loss of mitochondrial DNA in tolerant species (e.g., C. glabrata and Saccharomyces cerevisiae), also leads to high drug efflux via Pdr1 and drug resistance, but cellular fitness is highly compromised in these ‘petite’ isolates, which are therefore not thought to be clinically relevant. Heteroresistance (across top) is a semi-stable mechanism, often due to whole chromosome aneuploidy, that can confer either resistance (increased MIC), via increased expression of a target or of efflux pumps, or tolerance (susceptible MIC but increased growth in drug) via altered stress response pathways. Biofilms (bottom) are a sessile physiological state that grows slowly and exhibits drug resistance and/or tolerance due to multiple mechanisms, including sequestration of the drug by large amounts of extracellular matrix. Aneuploidy, gene amplification, copy number variation and loss of heterozygosity (LOH) can confer resistance or tolerance, depending on the specific genes and combinations of genes that are involved.

Fig. 2. Factors mediating the contribution of antifungal resistance to clinical failure.

All of the factors contributing to clinical failure in invasive fungal infection are also drivers of antifungal resistance.

Fig. 3. New antifungal drugs in the clinical pipeline.

Antifungals that are currently in phase 2 or 3 clinical trials for the treatment or prophylaxis of fungal infections. The antifungal names as well as other identifiers are provided, along with the clinical trial number and phase, and the types of fungal infections for enrolment. Information was obtained from ClinicalTrials.gov, a database of publicly and privately funded clinical studies (accessed June 27, 2022).