Sulfonylureas Have Antifungal Activity and Are Potent Inhibitors of Candida albicans Acetohydroxyacid Synthase

Lee, Yu-Ting; Cui, C. Q.; Chow, Eve W. L.; Pue, Nason; Lonhienne, Thierry; Wang, Jianguo; Fraser, James S.; Guddat, L.W.

doi:10.1021/jm301501k

Cited by 68 publications

(68 citation statements)

References 23 publications

(42 reference statements)

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“…50 The druggability of the M. tuberculosis AHAS has led to the screening and design of compounds targeting the enzyme of the bacilli, including ssDNA aptamers. 3,40,50-55 Many of these inhibitors are active against both the enzyme and resistant strains, with minimal inhibitory concentration (MIC) values similar to those of the standard antibiotics. 40,53 Molecular docking experiments revealed that most of these inhibitors likely bind outside of the active site, 53 in agreement with what was previously reported for SU herbicides.…”

Section: Ilvb/n Acetolactate (Acetohydroxyacid) Synthasementioning

confidence: 99%

Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

2017

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The eight enzymes responsible for the biosynthesis of the three branched-chain amino acids (l-isoleucine, l-leucine, and l-valine) were identified decades ago using classical genetic approaches based on amino acid auxotrophy. This review will highlight the recent progress in the determination of the three-dimensional structures of these enzymes, their chemical mechanisms, and insights into their suitability as targets for the development of antibacterial agents. Given the enormous rise in bacterial drug resistance to every major class of antibacterial compound, there is a clear and present need for the identification of new antibacterial compounds with nonoverlapping targets to currently used antibacterials that target cell wall, protein, mRNA, and DNA synthesis.

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Section: Ilvb/n Acetolactate (Acetohydroxyacid) Synthasementioning

confidence: 99%

Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

2017

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“…To date, according to statistics by the Herbicide Resistance Action Committee, more than 50 AHAS inhibitors are available for weed control and making great contributions to world agricultural production. Several AHAS inhibitors have also shown bacteriostatic effects on some pathogenic microorganisms, including Burkholderia pseudomallei, Pseudomonas aeruginosa, Acinetobacter baumannii and Candida albicans, indicating a promising antimicrobial drug strategy targeting enzymes involved in the BCAA biosynthesis pathway (Kreisberg et al, 2013;Lee et al, 2013). KARI, encoded by ILV5, is one step downstream from AHAS, and catalyses the conversion of 2-acetolactate and 2-aceto-2-hydroxybutyrate to 2,3-dihydroxyisoverate and 2,3-dihydroxy-3-methylvalerate, respectively, in the BCAA biosynthetic pathway.…”

Section: Introductionmentioning

confidence: 99%

FgIlv5 is required for branched-chain amino acid biosynthesis and full virulence in Fusarium graminearum

Liu

Wang

et al. 2014

Microbiology

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In this study, we characterized FgIlv5, a homologue of the Saccharomyces cerevisiae keto-acid reductoisomerase (KARI) from the important wheat head scab fungus Fusarium graminearum. KARI is a key enzyme in the branched-chain amino acid (BCAA, including leucine, isoleucine and valine) biosynthetic pathway that exists in a variety of organisms from bacteria to fungi and higher plants, but not in mammals. The FgILV5 deletion mutant DFgIlv5-4 failed to grow when the culture medium was nutritionally limited for BCAAs. When grown on potato-dextrose agar plates, DFgIlv5-4 exhibited a significant decrease in aerial hyphae formation and red pigmentation. Conidia formation was also blocked in DFgIlv5-4. Exogenous addition of 1 mM isoleucine and valine was able to rescue the defects of mycelial growth and conidial morphogenesis. Cellular stress assays showed that DFgIlv5-4 was more sensitive to osmotic and oxidative stresses than the wild-type strain. In addition, virulence of DFgIlv5-4 was dramatically reduced on wheat heads, and a low level of deoxynivalenol production was detected in DFgIlv5-4 in wheat kernels. The results of this study indicate that FgIlv5 is involved in valine and isoleucine biosynthesis and is required for full virulence in F. graminearum.

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“…Chlorimuron ethyl (CE) ( Fig. 1A), an SU herbicide, has previously been shown to inhibit the growth of C. albicans in culture with a minimum inhibitory concentration, 50% (MIC 50 ) of 2 μM (18), and several noncommercial TPs have activity against C. albicans, C. neoformans, and A. fumigatus with MIC 50 values in the range of 1-4 μg/mL (19). However, beyond these Significance Human fungal pathogens resistant to conventional therapeutics pose a major threat to global human health.…”

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confidence: 99%

Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

García

Chua

Low

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (Ki values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates.

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Sulfonylureas Have Antifungal Activity and Are Potent Inhibitors of Candida albicans Acetohydroxyacid Synthase

Cited by 68 publications

References 23 publications

Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

FgIlv5 is required for branched-chain amino acid biosynthesis and full virulence in Fusarium graminearum

Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

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