<i>In Vitro</i>
            and
            <i>In Vivo</i>
            Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

Upton, Anna M.; Cho, Sang Hyun; Yang, Tianjian; Kim, Y.; Wang, Y.; Lu, Yu; Wang, B.; Xu, Jian; Mdluli, Khisimuzi; Ma, Zhenkun; Franzblau, Scott G.

doi:10.1128/aac.03823-14

Cited by 83 publications

(65 citation statements)

References 33 publications

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“…In this first round of evaluation, small functional groups, different in electronic nature and physicochemical characteristics, were used to decorate the phenyl rings at various positions. Regarding the 4-phenyl moiety, a compound bearing a nitro group was selected (4), as it is a common substituent in some of the most advanced antituberculars in the pipeline (PA-824 [34] and TBA-354 [35]). The methoxy group (5, 6) was selected as in the parental series previously reported ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Discovery of antitubercular 2,4-diphenyl-1H-imidazoles from chemical library repositioning and rational design

Pieroni

Wan

Zuliani

et al. 2015

European Journal of Medicinal Chemistry

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Section: Resultsmentioning

confidence: 99%

Discovery of antitubercular 2,4-diphenyl-1H-imidazoles from chemical library repositioning and rational design

Pieroni

Wan

Zuliani

et al. 2015

European Journal of Medicinal Chemistry

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“…25 Verapamil was used as a positive control in the assay. Upon terminating the incubations by the addition of acetonitrile, the extract was analyzed by LC/MS/MS to determine the remaining concentration of terreic acid.…”

Section: In Vitro Metabolismmentioning

confidence: 99%

Escherichia coli N-Acetylglucosamine-1-Phosphate-Uridyltransferase/Glucosamine-1-Phosphate-Acetyltransferase (GlmU) Inhibitory Activity of Terreic Acid Isolated from Aspergillus terreus

et al. 2016

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Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the acetyltransferase domain of a bifunctional enzyme, Escherichia coli N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the acetyltransferase domain of E. coli GlmU with an IC 50 of 44.24 ± 1.85 µM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4× minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the acetyltransferase domain of GlmU. Terreic acid was also found to be metabolically stable in the in vitro incubations with rat liver microsome in the presence of a NADPH regenerating system. The studies reported here suggest that terreic acid is a potent antimicrobial agent and support that E. coli GlmU acetyltransferase is a molecular target of terreic acid, resulting in its antibacterial activity.

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“…We evaluated the efficacy of TCA007 against Mtb Erdman in acute and chronic BALB/c mouse low dose aerosol infection models 8. After treatment for 3 weeks during the acute phase of infection with TCA007 at a dose of 50 mg kg −1 and 100 mg kg −1 body weight, a dose‐dependent in vivo efficacy was observed with reduction of bacterial load in lung by 1.7 and 2.3 log 10 CFU, respectively (Figure 3 A and SI methods).…”

mentioning

confidence: 99%

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

et al. 2017

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Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X‐ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1–TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

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In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

Cited by 83 publications

References 33 publications

Discovery of antitubercular 2,4-diphenyl-1H-imidazoles from chemical library repositioning and rational design

Discovery of antitubercular 2,4-diphenyl-1H-imidazoles from chemical library repositioning and rational design

Escherichia coli N-Acetylglucosamine-1-Phosphate-Uridyltransferase/Glucosamine-1-Phosphate-Acetyltransferase (GlmU) Inhibitory Activity of Terreic Acid Isolated from Aspergillus terreus

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

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