Chitin Synthesis as a Target for Antifungal Drugs

Abstract

Human mycoses have become a threat to health world-wide. Unfortunately there are only a limited number of antimycotic drugs in use. Promising targets for drugs specific against fungi are those affecting chitin synthesis. Chitin is absent in vertebrates, and is essential for fungal wall integrity. A thorough knowledge of the mechanism of chitin synthesis is required to design specific inhibitors. We review here our current understanding of the process, and the most promising drugs that inhibit it. Chitin is made by chitin synthases requiring specific microvesicles, the chitosomes, for intracellular transport. Fungi contain several chitin synthases, some of which may be essential at a certain stage. This phenomenon is important to take into account for drug design. The most widely studied chitin synthase inhibitors are polyoxins and nikkomycins that probably bind to the catalytic site of chitin synthases. These are not equally susceptible to the drugs. In Saccharomyces cerevisiae the order of sensitivity is: Chs3p>Chs1p>Chs2p. Main problems for their succesful use in vivo are: low permeability, and different susceptibility of fungal species, and variable responses in animal models. Chemical modifications have been proposed to make more potent derivatives. Other synthetic or natural compounds are also promising as possible inhibitors, but their properties are less well known. Rational drug design has proceeded only on the basis of existing inhibitors, because the structure of the active site of chitin synthase is unknown. Undoubtedly, determination of this, and the biosynthetic mechanism will reveal unexpected drug targets in the future.

Chitin metabolism in insects: structure, function and regulation of chitin synthases and chitinases

“…They competitively inhibit both fungal and insect chitin synthases. It is believed that inhibition occurs via binding to the catalytic site (Ruiz-Herrera and San-Blas, 2003). Polyoxins have found some applications in the control of phytopathogens, whereas the commercial application of nikkomycins is pending, although they seem to be more potent inhibitors than polyoxins (Cohen and Casida, 1980a;Zhang and Miller, 1999;Tellam et al, 2000).…”

“…Polyoxins have found some applications in the control of phytopathogens, whereas the commercial application of nikkomycins is pending, although they seem to be more potent inhibitors than polyoxins (Cohen and Casida, 1980a;Zhang and Miller, 1999;Tellam et al, 2000). Generally, the application of peptidyl nucleosides is complicated by low permeability, hydrolytic lability, varying susceptibility of fungal species and the multitude of responses found in animals (Zhang and Miller, 1999;Ruiz-Herrera and San-Blas, 2003).…”

Resistance mutation conserved between insects and mites unravels the benzoylurea insecticide mode of action on chitin biosynthesis

“…IGRs are a group of chemically diverse compounds including the microbial-derived pyrimidine-nucleoside peptides, benzoylureas (BPUs), oxazolines, and thiadiazines (6) that all interfere with chitin biosynthesis or transport and deposition pathways. The MoA of the antifungal pyrimidine-nucleoside antibiotics is by their function as substrate analogs of UDP-N-acetylglucosamine at the catalytic site of chitin synthase (CHS) and are thus considered competitive inhibitors (7)(8)(9). BPUs (10), such as the major mosquito larvicide diflubenzuron and the agriculturally widely used insecticides triflumuron and lufenuron, represent a group of compounds (group 15 with regard to the IRAC grouping system; see also Fig.…”

Inhibition of Chitin Synthases and Antifungal Activities by 2'-Benzoyloxycinnamaldehyde from Pleuropterus ciliinervis and Its Derivatives

“…5) Chitin is absent from plant and mammalian species, while it is abundant in arthropods, most fungi, and other eukaryotes. 6) Mutations that affect chitin synthesis cause osmotic sensitivity, 7) abnormal morphology, aggregation, and growth arrest with elongated buds. 8,9) Thus, its biosynthesis has become a more and more attractive target for the design of antifungal agents.…”