Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109: Bacterial and Protozoal Cell Growth Inhibitors

Li, Kai; Wang, Yan; Yang, Gyongseon; Byun, Sooyoung; Rao, Guodong; Shoen, Carolyn; Yang, Hongliang; Gulati, Anmol; Crick, Dean C.; Cynamon, Michael H.; Huang, Guozhong; Docampo, Roberto; No, Joo Hwan; Oldfield, Eric

doi:10.1021/acsinfecdis.5b00026

Cited by 33 publications

(38 citation statements)

References 15 publications

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“…Hitting numerous targets has several repercussions in drug research and development. It broadens the antimicrobial spectrum, as reported for SQ109 52 , nitazoxanide 53 and 2-AI compounds 54 . Furthermore, it decreases the likelihood of selecting for resistant mutants.…”

Section: Discussionsupporting

confidence: 60%

2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain

Jeon

Ackart

et al. 2019

Sci Rep

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There is an urgent need to develop new drugs against tuberculosis. In particular, it is critical to target drug tolerant Mycobacterium tuberculosis (M. tuberculosis), responsible, in part, for the lengthy antibiotic regimen required for treatment. We previously postulated that the presence of in vivo biofilm-like communities of M. tuberculosis could contribute to this drug tolerance. Consistent with this hypothesis, certain 2-aminoimidazole (2-AIs) molecules with anti-biofilm activity were shown to revert mycobacterial drug tolerance in an in vitro M. tuberculosis biofilm model. While exploring their mechanism of action, it was serendipitously observed that these 2-AI molecules also potentiated β-lactam antibiotics by affecting mycobacterial protein secretion and lipid export. As these two bacterial processes are energy-dependent, herein it was evaluated if 2-AI compounds affect mycobacterial bioenergetics. At low concentrations, 2B8, the lead 2-AI compound, collapsed both components of the proton motive force, similar to other cationic amphiphiles. Interestingly, however, the minimum inhibitory concentration of 2B8 against M. tuberculosis correlated with a higher drug concentration determined to interfere with the mycobacterial electron transport chain. Collectively, this study elucidates the mechanism of action of 2-AIs against M. tuberculosis, providing a tool to better understand mycobacterial bioenergetics and develop compounds with improved anti-mycobacterial activity.

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Section: Discussionsupporting

confidence: 60%

2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain

Jeon

Ackart

et al. 2019

Sci Rep

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“…Mycolic acids and the MmpL3 protein are not present in S. aureus and E. coli, so it is likely that an alternative cellular process in these organisms is targeted by the investigated compounds. Similarly, it was reported that SQ109, an inhibitor of MmpL3 in M. tuberculosis, displayed bactericidal activity against Helicobacter pylori and Trypanosoma brucei, organisms lacking the mmpL3 gene (55,56). Another MmpL3 inhibitor, the pyrrole derivative BM212 (45), was also identified as a compound with good activity against Candida albicans (57).…”

Section: Discussionmentioning

confidence: 85%

1 H -Benzo[ d ]Imidazole Derivatives Affect MmpL3 in Mycobacterium tuberculosis

Korycka-Machała

Viljoen

Pawełczyk

et al. 2019

Antimicrob Agents Chemother

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1H-benzo[d]imidazole derivatives exhibit antitubercular activity in vitro at a nanomolar range of concentrations and are not toxic to human cells, but their mode of action remains unknown. Here, we showed that these compounds are active against intracellular Mycobacterium tuberculosis. To identify their target, we selected drug-resistant M. tuberculosis mutants and then used whole-genome sequencing to unravel mutations in the essential mmpL3 gene, which encodes the integral membrane protein that catalyzes the export of trehalose monomycolate, a precursor of the mycobacterial outer membrane component trehalose dimycolate (TDM), as well as mycolic acids bound to arabinogalactan. The drug-resistant phenotype was also observed in the parental strain overexpressing the mmpL3 alleles carrying the mutations identified in the resistors. However, no cross-resistance was observed between 1H-benzo[d]imidazole derivatives and SQ109, another MmpL3 inhibitor, or other first-line antitubercular drugs. Metabolic labeling and quantitative thin-layer chromatography (TLC) analysis of radiolabeled lipids from M. tuberculosis cultures treated with the benzoimidazoles indicated an inhibition of trehalose dimycolate (TDM) synthesis, as well as reduced levels of mycolylated arabinogalactan, in agreement with the inhibition of MmpL3 activity. Overall, this study emphasizes the pronounced activity of 1H-benzo[d]imidazole derivatives in interfering with mycolic acid metabolism and their potential for therapeutic application in the fight against tuberculosis.

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“…Based on the HEK293 activity, the compound was selective for all four parasites but only showed a marginal window with respect to HEPG2 activity. SQ-109 has been extensively studied for T. cruzi , T. brucei brucei , and L. donovani ; therefore, further studies on this compound may be of limited benefit ( 63 , 64 ). MMV687248, a 3,5-disubstituted pyridine with an IC 50 of 1.05 μM against T. brucei brucei with a selectivity index (SI) of >20 against both HEK293 and HEPG2, is an interesting novel starting point for HAT drug discovery.…”

Section: Discussionmentioning

confidence: 99%

Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery

Duffy

Sykes

Jones

et al. 2017

Antimicrob Agents Chemother

127

146

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Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro. Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research.

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Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109: Bacterial and Protozoal Cell Growth Inhibitors

Cited by 33 publications

References 15 publications

2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain

2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain

1 H -Benzo[ d ]Imidazole Derivatives Affect MmpL3 in Mycobacterium tuberculosis

Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery

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