Abstract
Antifungal drugs and antifungal agrochemicals have significant limitations. These include several unintended consequences of their use including the growing importance of intrinsic and acquired resistance. These problems underpin an increasingly urgent need to improve the existing classes of antifungals and to discover novel antifungals. Structural insights into drug targets and their complexes with both substrates and inhibitory ligands increase opportunity for the discovery of more effective antifungals. Implementation of this promise, which requires multiple skill sets, is beginning to yield candidates from discovery programs that could more quickly find their place in the clinic. This review will describe how structural biology is providing information for the improvement and discovery of inhibitors targeting the essential fungal enzyme sterol 14α-demethylase.
Highlights
The most important members of the latter group include the polyenes, azoles, echinocandins, allylamines and pyrimidine analogs used against human pathogens while the azoles, succinate dehydrogenase inhibitors, anilinopyrimidines, coenzyme Q inhibitors, morpholines and methyl-benzimidazole carbamates have been used widely as pesticides directed against plant pathogens [2]
This is especially problematic for the existing azole pesticides that appear to have driven the selection worldwide of A. fumigatus strains resistant to azoles used in the clinic
We focus in brief on two major examples: Z. tritici and P. pachyrhizi
Summary
The remarkable genetic and phenotypic diversity of fungal pathogens, the multifaceted relationships and genetic similarities these eukaryotes share with their human or agricultural hosts, as well as the economic costs of antifungal development, make the urgently needed expansion of the current armamentarium of antifungal drugs and fungicidal agrochemicals a daunting challenge [1,2,3]. Data Bank (PDB) of pertinent high resolution structures of drug targets and their host homologues, including the conformations adopted by inhibitory ligands in complex with their targets, plus off-target structural insights, complement and focus drug discovery paradigms Such paradigms include the use of phenotypic screens with genetically engineered target constructs as a prelude to studies with more complex clinical or field isolates of disease causing fungi. Downstream of drug discovery, the application in the clinic or field of novel classes of antifungals is likely to remain a complex and long-term aspiration for most academics and biotechnology companies This is because the skills and economic resources of the pharmaceutical or agrochemical industries are needed to address the multiple requirements of drug development. Of particular importance is the judicious use of prophylaxis, prevention and treatment strategies that minimize opportunity for the development and expansion of drug resistance, and to plan for and be able to apply practical alternative therapies should resistance occur
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