Triazolopyrimidine herbicides are potent inhibitors of Aspergillus fumigatus acetohydroxyacid synthase and potential antifungal drug leads

Abstract

Aspergillus fumigatus is a fungal pathogen whose effects can be debilitating and potentially fatal in immunocompromised patients. Current drug treatment options for this infectious disease are limited to just a few choices (e.g. voriconazole and amphotericin B) and these themselves have limitations due to potentially adverse side effects. Furthermore, the likelihood of the development of resistance to these current drugs is ever present. Thus, new treatment options are needed for this infection. A new potential antifungal drug target is acetohydroxyacid synthase (AHAS; EC 2.2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway, and a target for many commercial herbicides. In this study, we have expressed, purified and characterised the catalytic subunit of AHAS from A. fumigatus and determined the inhibition constants for several known herbicides. The most potent of these, penoxsulam and metosulam, have Ki values of 1.8 ± 0.9 nM and 1.4 ± 0.2 nM, respectively. Molecular modelling shows that these compounds are likely to bind into the herbicide binding pocket in a mode similar to Candida albicans AHAS. We have also shown that these two compounds inhibit A. fumigatus growth at a concentration of 25 µg/mL. Thus, AHAS inhibitors are promising leads for the development of new anti-aspergillosis therapeutics.

Molecular Targets of Herbicides and Fungicides─Are There Useful Overlaps for Fungicide Discovery?

“…As reviewed by Justrzębowska and Gabriel, all of the published attempts to discover fungicides acting on ALS have been directed toward medicinal fungicides . Recent work has reported that commercial ALS-inhibiting herbicides are promising leads for pharmaceutical fungicides. − The natural ALS inhibitor harzianic acid (Figure and ) is effective on the ALS of the fungal plant pathogens Fusarium oxysporum and Sclerotinia sclerotiorum , but not that of plant ( Arabidopsis ) ALS, suggesting that a fungicidal ALS inhibitor could be designed for agricultural use with no crop injury problems. Alternatively, crops can easily be made resistant to ALS inhibitors by mutation breeding, allowing for a product that could target ALS in both weeds and plant pathogens, thus lowering the overall pesticide load in the environment.…”

First Clarification of the Involvement of Glycosyltransferase MdUGT73CG22 in the Detoxification Metabolism of Nicosulfuron in Apple

“…Among them, triazolopyrimidine sulfonamides are a new class of acetolactate synthetase (ALS) inhibitors that have been developed and rapidly applied since the 1990s. By modifying sulfonylureas, they have retained the advantage of ultra-high efficiency while solving the obvious disadvantage that some varieties have a long residual time in the soil, which can cause damage to the subsequent crop, and have thus become the first choice among the five subclasses of herbicides [5].…”

T-cell epitope-based vaccine prediction against Aspergillus fumigatus: a harmful causative agent of aspergillosis

“…Only a few drugs (such as voriconazole and amphotericin B) are now available to treat this invasive condition, and even these have restrictions owing to potential risks, and so, these drugs hold longer duration of treatment with side effects [6], so we tried to explore more best possible options of epitopes by deploying approaches of immunoinformatics. In current study, we targeted variety of proteins from A. fumigatus to screen out immunogenic T-cell epitopes against A. fumigatus fungi.…”