Killing Two Birds with One Stone: Discovery of Dual Inhibitors of Oxygen and Fumarate Respiration in Zoonotic Parasite, Echinococcus multilocularis

Enkai, Shigehiro; Kouguchi, Hirokazu; Inaoka, Daniel Ken; Shiba, T.; Hidaka, Masahito; Matsuyama, Hiroyuki; Sakura, Takaya; Yagi, Kinpei; Kita, Kiyoshi

doi:10.1128/aac.01428-22

Cited by 5 publications

(9 citation statements)

References 34 publications

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“…It is worth mentioning that the inhibition of NADH-fumarate reductase by ascochlorin was more pronounced than expected ( Table 2 ). A recent study ( Enkai et al., 2023 ) showed that ascofuranone, an analog of ascochlorin, effectively inhibited complex II of E. multilocularis . These results suggest that ascochlorin analogs may inhibit complex II of parasitic platyhelminths.…”

Section: Discussionmentioning

confidence: 99%

“…The inhibition of complex I by rotenone also affected fumarate respiration and killed NEJs ( Figure 4 ). An unexpected effect of ascochlorin on NEJs under the anaerobic conditions ( Figure 4 ) was probably due to its inhibitory activity against complex II (72.3%) ( Table 2 ) ( Enkai et al., 2023 ). The present study revealed that NEJs can use both oxygen and fumarate respiration ( Figure 1 ), depending on oxygen availability.…”

Section: Discussionmentioning

confidence: 99%

“…In conclusion, we demonstrated that both oxygen and fumarate respiration can be differentially utilized by NEJs, depending on the oxygen availability in the environment, according to the migration route within the host ( Figure 2 ). We have shown the active hybrid respiration in the helminths, including A. suum ( Iwata et al., 2008 ) and E. multirocularis ( Enkai et al., 2023 ), whose adult habitats were low-oxygen conditions, and this is a common adaptation strategy of the parasites. As shown by the hrCNE analysis in the present study, it may be a diverse property acquired by each parasite as it evolves and adapts to its host environment, suggesting that fumarate respiration has evolved independently in each of the parasites.…”

Section: Discussionmentioning

confidence: 99%

“…The enzyme activity assays and inhibitor effects were essentially performed in accordance with previous reports with slight modifications ( Omura et al., 2001 ; Matsumoto et al., 2008 ; Enkai et al., 2023 ). Assays utilizing the adult mitochondrial fractions were carried out in a 1 mL reaction mixture at 25°C.…”

Section: Methodsmentioning

confidence: 99%

“…Mammalian mitochondria normally lack this system. Therefore, NADH-fumarate reductase has been proposed as a promising drug target for developing novel anthelmintics ( Omura et al., 2001 ; Kita et al., 2003 ; Matsumoto et al., 2008 ; Enkai et al., 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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Fumarate respiration of Fasciola flukes as a potential drug target

Tashibu,

Inaoka,

Sakamoto

et al. 2024

Front. Cell. Infect. Microbiol.

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Fascioliasis is a neglected tropical zoonotic disease caused by liver flukes belonging to the genus Fasciola. The emergence of resistance to triclabendazole, the only World Health Organization-recommended drug for this disease, highlights the need for the development of new drugs. Helminths possess an anaerobic mitochondrial respiratory chain (fumarate respiration) which is considered a potential drug target. This study aimed to evaluate the occurrence of fumarate respiration in Fasciola flukes. We analyzed the properties of the respiratory chain of Fasciola flukes in both adults and newly excysted juveniles (NEJs). Fasciola flukes travel and mature through the stomach, bowel, and abdominal cavity to the liver, where oxygen levels gradually decline. High fumarate reductase activity was observed in the mitochondrial fraction of adult Fasciola flukes. Furthermore, rhodoquinone-10 (RQ10 Em’= −63 mV), a low-potential electron mediator used in fumarate respiration was found to be predominant in adults. In contrast, the activity of oxygen respiration was low in adults. Rotenone, atpenin A5, and ascochlorin, typical inhibitors of mitochondrial enzymes in complexes I, II, and III, respectively, inhibit the activity of each enzyme in the adult mitochondrial fraction. These inhibitors were then used for in vitro viability tests of NEJs. Under aerobic conditions, NEJs were killed by rotenone or ascochlorin, which inhibit aerobic respiration (complex I–III), whereas atpenin A5, which inhibits complex II involved in fumarate respiration, did not affect NEJs. Moreover, ubiquinone-10 (UQ10 Em’= +110 mV), which is used in oxidative respiration, was detected in NEJs, in addition to RQ10. In contrast, under anaerobic conditions, rotenone and atpenin A5, which inhibit fumarate respiration (complex I–II), were crucial for NEJs. These findings demonstrate that NEJs have active hybrid respiration, in which they can properly use both oxygen and fumarate respiration, depending on oxygen availability. Thus, fumarate respiration is a promising drug target for Fasciola flukes, because it plays an essential role in both adults and NEJs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Fumarate respiration of Fasciola flukes as a potential drug target

Tashibu,

Inaoka,

Sakamoto

et al. 2024

Front. Cell. Infect. Microbiol.

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Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase

Adolph,

Hards,

Williams

et al. 2024

ACS Infect. Dis.

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Drug-resistant Mycobacterium tuberculosis is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in M. tuberculosis, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of M. tuberculosis. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against M. tuberculosis.

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Recent Advances in Chemistry and Bioactivities of Secondary Metabolites from the Genus Acremonium

Qin,

Lu,

et al. 2024

JoF

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Acremonium fungi is one of the greatest and most complex genera in Hyphomycetes, comprising 130 species of marine and terrestrial sources. The past decades have witnessed substantial chemical and biological investigations on the diverse secondary metabolites from the Acremonium species. To date, over 600 compounds with abundant chemical types as well as a wide range of bioactivities have been obtained from this genus, attracting considerable attention from chemists and pharmacologists. This review mainly summarizes the sources, chemical structures, and biological activities of 115 recently reported new compounds from the genus Acremonium from December 2016 to September 2023. They are structurally classified into terpenoids (42%), peptides (29%), polyketides (20%), and others (9%), among which marine sources are predominant (68%). Notably, these compounds were primarily screened with cytotoxic, antibacterial, and anti-inflammatory activities. This paper provides insights into the exploration and utilization of bioactive compounds in this genus, both within the scientific field and pharmaceutical industry.

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Killing Two Birds with One Stone: Discovery of Dual Inhibitors of Oxygen and Fumarate Respiration in Zoonotic Parasite, Echinococcus multilocularis

Cited by 5 publications

References 34 publications

Fumarate respiration of Fasciola flukes as a potential drug target

Fumarate respiration of Fasciola flukes as a potential drug target

Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase

Recent Advances in Chemistry and Bioactivities of Secondary Metabolites from the Genus Acremonium

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