Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance

Abstract

The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

FIG. 1

Structures of representative antifungal agents.

FIG. 2

Ergosterol biosynthetic pathway. Steps at which various antifungal agents exert their inhibitory activities are shown. TERB, terbinafine; FLU, fluconazole; ITRA, itraconazole; VOR, voriconazole.

FIG. 3

Mechanisms by which microbial cells might develop resistance. 1, The target enzyme is overproduced, so that the drug does not inhibit the biochemical reaction completely. 2, The drug target is altered so that the drug cannot bind to the target. 3, The drug is pumped out by an efflux pump. 4, The entry of the drug is prevented at the cell membrane/cell wall level. 5, The cell has a bypass pathway that compensates for the loss-of-function inhibition due to the drug activity. 6, Some fungal “enzymes” that convert an inactive drug to its active form are inhibited. 7, The cell secretes some enzymes to the extracellular medium, which degrade the drug.

FIG. 4

Relationship between MIC, fluconazole dose, and emergence of resistance in oropharyngeal candidiasis. ○, MIC of fluconazole for the clinical isolate; ■, effective daily dose of fluconazole. MICs are represented on the secondary y axis, in logarithmic scale. Boxes above the graph represent genetic changes identified at each stage. Based on data from references and .

FIG. 5

Schematic representation of the interaction between amphotericin B and cholesterol in a phospholipid bilayer. (A) The conducting pore is formed by the end-to-end union of two wells or half pores. Adapted from reference with permission of the publisher. (B) Molecular orientation in an amphotericin B-cholesterol pore. The dotted lines between the hydrocarbon chains of phospholipids represent short-range London-van der Waals forces. The dashed lines represent hydrogen bonds formed between amphotericin B and cholesterol molecules.