Growth Inhibition of Pathogenic Bacteria by Sulfonylurea Herbicides

Kreisberg, Jason F.; Ong, Nicholas T.; Krishna, Aishwarya; Joseph, Thomas L.; Wang, Jing; Ong, Catherine; Ooi, Hui Ann; Sung, Julie C.; Siew, Chern Chiang; Chang, Grace; Biot, Fabrice; Cuccui, Jon; Wren, Brendan W.; Chan, Joey; Sivalingam, Suppiah P.; Zhang, Lian-Hui; Verma, Chandra; Tan, Patrick

doi:10.1128/aac.02327-12

Cited by 20 publications

(15 citation statements)

References 38 publications

(27 reference statements)

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“…6B). Previous studies have shown that the SUs are readily absorbed following oral administration (17,39); therefore, here we additionally show that i.p. injection is also a viable route for drug administration.…”

Section: Resultssupporting

confidence: 74%

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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Section: Resultssupporting

confidence: 74%

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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“…In the AHAS III operon of both B. pseudomallei K96243 and MSHR668 there also appears to be a third gene (ilvC) that codes for a keto-acid reductoisomerase, which was pointed out previously [51]. The presence of AHAS III in B. pseudomallei K96243 was also reported by Kreisberg et al [52] while looking for inhibitors for BCAA in pathogenic bacteria.…”

Section: Discussionsupporting

confidence: 52%

Deletion of Two Genes in Burkholderia pseudomallei MSHR668 That Target Essential Amino Acids Protect Acutely Infected BALB/c Mice and Promote Long Term Survival

et al. 2019

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Melioidosis is an emerging disease that is caused by the facultative intracellular pathogen Burkholderia pseudomallei. It is intrinsically resistant to many antibiotics and host risk factors play a major role in susceptibility to infection. Currently, there is no human or animal vaccine against melioidosis. In this study, multiple B. pseudomallei MSHR668 deletion mutants were evaluated as live attenuated vaccines in the sensitive BALB/c mouse model of melioidosis. The most efficacious vaccines after an intraperitoneal challenge with 50-fold over the 50% median lethal dose (MLD50) with B. pseudomallei K96243 were 668 ΔhisF and 668 ΔilvI. Both vaccines completely protected mice in the acute phase of infection and showed significant protection (50% survivors) during the chronic phase of infection. The spleens of the survivors that were examined were sterile. Splenocytes from mice vaccinated with 668 ΔhisF and 668 ΔilvI expressed higher amounts of IFN-γ after stimulation with B. pseudomallei antigens than splenocytes from mice vaccinated with less protective candidates. Finally, we demonstrate that 668 ΔhisF is nonlethal in immunocompromised NOD/SCID mice. Our results show that 668 ΔhisF and 668 ΔilvI provide protective cell-mediated immune responses in the acute phase of infection and promote long term survival in the sensitive BALB/c mouse model of melioidosis.

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“…Recent reports regarding the bacteriostatic effects of several AHAS inhibitors on some pathogenic bacteria (Kreisberg et al, 2013;Lee et al, 2013) have highlighted the potential of antimicrobial drug strategies targeting BCAA biosynthetic enzymes and the urgent need for identification of essential ILV genes in important human and plant pathogenic micro-organisms. Previous work in S. cerevisiae and Cryptococcus neoformans showed that AHAS-encoding gene ILV2 deletion mutants exhibited amino acid starvation and are unable to survive in vivo and/or are avirulent (Kingsbury et al, 2004(Kingsbury et al, , 2006.…”

Section: Discussionmentioning

confidence: 99%

“…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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Growth Inhibition of Pathogenic Bacteria by Sulfonylurea Herbicides

Cited by 20 publications

References 38 publications

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

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

Deletion of Two Genes in Burkholderia pseudomallei MSHR668 That Target Essential Amino Acids Protect Acutely Infected BALB/c Mice and Promote Long Term Survival

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

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