Antifungal Agents and Resistance
Antifungal agents are the drugs used to treat infections caused by fungi, and antifungal resistance is the corresponding loss of drug activity that arises when fungi acquire or express mechanisms that defeat these agents. Together they form a compact but high-stakes area of medical mycology, because the eukaryotic biology fungi share with their human hosts leaves comparatively few selectively toxic drug targets.
Definition
Antifungal agents are compounds that selectively inhibit or kill fungi by targeting fungus-specific structures or pathways, chiefly the ergosterol of the fungal membrane or the beta-glucan of the fungal cell wall; antifungal resistance is the reduced susceptibility of a fungus to a drug to which it was, or would be expected to be, sensitive.
Scope
This area orients the reader to the principal classes of antifungal drugs (azoles, polyenes, echinocandins, and antimetabolites), the molecular targets they exploit, the mechanisms by which fungi become resistant, and the pharmacokinetic and toxicity considerations that shape how the drugs behave. It is a reference overview of how the agents and resistance are understood and studied, not clinical guidance for prescribing.
Sub-topics
Core questions
- What fungus-specific targets allow a drug to harm the fungus while sparing the human host?
- By what molecular mechanisms do fungi resist each antifungal class?
- Why is the antifungal armamentarium so much smaller than the antibacterial one?
- How do pharmacokinetics and toxicity constrain the use of antifungal drugs?
Key concepts
- Ergosterol as the shared target of azoles and polyenes
- Beta-(1,3)-glucan synthase as the echinocandin target
- Selective toxicity in a eukaryotic pathogen
- Fungistatic versus fungicidal activity
- Target alteration, target overexpression, and efflux as resistance routes
- Minimum inhibitory concentration (MIC) and breakpoints
- Emerging multidrug-resistant species
Mechanisms
Most clinically important antifungals exploit one of two fungus-specific features. The azoles and polyenes both act on ergosterol, the principal sterol of the fungal membrane: azoles inhibit its biosynthesis (the enzyme lanosterol 14-alpha-demethylase, encoded by ERG11/CYP51), while polyenes such as amphotericin B bind ergosterol directly and disrupt the membrane. The echinocandins instead inhibit beta-(1,3)-glucan synthase, crippling cell-wall construction, while the antimetabolite flucytosine interferes with fungal nucleic acid synthesis. Resistance arises through alteration or overexpression of the drug target, up-regulation of efflux pumps that expel azoles, and adaptive stress responses; these routes are reviewed across drug classes by Ghannoum and Rice (1999) and Cowen and colleagues (2014).
Clinical relevance
Understanding antifungal classes and resistance underpins how invasive fungal infections are diagnosed, monitored, and studied, and how susceptibility testing is interpreted. The narrowness of the antifungal repertoire and the spread of resistant organisms make this area increasingly important to public health; the material here describes how the agents and their failure are understood and is not a basis for individual prescribing or dosing decisions.
Epidemiology
Antifungal resistance is a growing global concern: azole-resistant Aspergillus fumigatus and multidrug-resistant species such as Candida auris have spread across multiple regions, and resistance now complicates the management of invasive candidiasis and aspergillosis (Perlin et al., 2017). The limited number of drug classes magnifies the impact of resistance in any one of them.
History
Antifungal therapy began in the mid-twentieth century with amphotericin B and flucytosine, expanded substantially with the introduction of the triazoles in the 1980s and 1990s, and gained the echinocandins around the turn of the century. As use widened, resistance followed, and the synthesis of mechanism across classes by Ghannoum and Rice (1999) marked the maturation of antifungal pharmacology as a coherent field.
Key figures
- Mahmoud Ghannoum
- Leah Cowen
- David Perlin
- Dominique Sanglard
- Russell Lewis
Related topics
Seminal works
- ghannoum-rice-1999
- cowen-2014
- perlin-2017
Frequently asked questions
- Why are there so few antifungal drug classes compared with antibiotics?
- Fungi are eukaryotes and share much of their cell biology with human cells, so there are relatively few structures or pathways a drug can attack in the fungus without also harming the host. This narrows the field to a handful of selectively toxic targets, mainly the fungal membrane sterol ergosterol and the cell-wall polymer beta-glucan.
- What is the difference between an antifungal agent and antifungal resistance?
- An antifungal agent is a drug that inhibits or kills fungi; antifungal resistance is the reduced susceptibility of a fungus to such a drug, arising when the organism acquires or expresses mechanisms that blunt the drug's effect.