Dataset Information

Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII₂CIV₂ Supercomplex Binding, and In Vitro Antimycobacterial Activity.

ABSTRACT: Q203 (telacebec) is an imidazopyridine amide (IPA) targeting the respiratory CIII₂CIV₂ supercomplex of the mycobacterial electron transport chain (ETC). Aiming for a better understanding of the molecular mechanism of action of IPA, 27 analogues were prepared through a seven-step synthetic scheme. Oxygen consumption assay was designed to test the inhibition of purified Mycobacterium smegmatis CIII₂CIV₂ by these compounds. The assay results generally supported structure-activity relationship information obtained from the structure of M. smegmatis CIII₂CIV₂ bound to Q203. The IC₅₀ of Q203 and compound 27 was 99 ± 32 and 441 ± 138 nM, respectively. All IPAs including Q203 showed no inhibition of mitochondrial ETC, proving their selectivity against mycobacteria. In vitro Mycobacterium tuberculosis growth inhibition and M. smegmatis CIII₂CIV₂ binding did not correlate perfectly. These observations suggest that further investigation into the mechanisms of resistance in different mycobacterial species is needed to understand the lack of the correlation pattern between CIII₂CIV₂ inhibition and cellular activity.

SUBMITTER: Abdelaziz R

PROVIDER: S-EPMC10233671 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII2CIV2 Supercomplex Binding, and In Vitro Antimycobacterial Activity.

Abdelaziz Rana R Di Trani Justin M JM Sahile Henok H Mann Lea L Richter Adrian A Liu Zhongle Z Bueler Stephanie A SA Cowen Leah E LE Rubinstein John L JL Imming Peter P

ACS omega 20230518 21

Q203 (telacebec) is an imidazopyridine amide (IPA) targeting the respiratory CIII2CIV2 supercomplex of the mycobacterial electron transport chain (ETC). Aiming for a better understanding of the molecular mechanism of action of IPA, 27 analogues were prepared through a seven-step synthetic scheme. Oxygen consumption assay was designed to test the inhibition of purified Mycobacterium smegmatis CIII2CIV2 by these compounds. The assay results genera ...[more]

PMID: 37273644

Similar Datasets

Project description:The traditional diagnostic tests for tuberculosis consist of an acid fast stain and a culture test from a sputum sample. With the emergence of drug resistant strains of tuberculosis, nucleic acid amplification has become the diagnostic test of choice. The nucleic acid amplification test consists of four steps: sputum sample collection, lysis of bacilli to release DNA, DNA amplification by PCR and detection of PCR products. The DNA extraction step has been largely overlooked and this study describes a systematic approach to measure the kinetics of cell lysis in a Tris-EDTA buffer. Mycobacterium smegmatis is a saphorytic, fast-growing mycobacterium that is often used as a surrogate of Mycobacterium tuberculosis in laboratory studies. M. smegmatis cells have been transformed with green fluorescent protein (GFP) genes. Transformed cells are lysed in a temperature-controlled cuvette that is equipped with optical input/output. The fluorescence signal increases when the GFP is released from lysed cells, and the extent of lysis of the loaded cells can be followed in real time. The experimental results are complemented by two theoretical models. The first model is based on a Monte Carlo simulation of the lysis process and the accompanying probability density function as described by the Fokker-Planck equation. The second model follows a chemical reaction engineering approach: the cell wall is modeled as layers, where each layer is made up of 'blocks'. Blocks can only be removed if they are exposed to the lysis solution and the model describes the rate of block exposure and removal. Both models are consistent with the experimental results. The main findings are: (1) the activation energy for M. smegmatis lysis by Tris-EDTA buffer is 22.1kcal/mole, (2) cells lyse on the average after 14-17% loss in cell wall thickness locally, (3) with the help of the models, the initial distribution in cell wall thickness of the population can be resolved, (4) near complete lysis of the cells is accomplished in 200 seconds at 80°C (90 seconds at 90°C). The results can be used to design an optimal lysis protocol that compromises between shorter processing times at higher temperature and reduced thermal damage to DNA at lower temperature.

Dataset Information

Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII₂CIV₂ Supercomplex Binding, and In Vitro Antimycobacterial Activity.

Publications

Imidazopyridine Amides: Synthesis, <i>Mycobacterium smegmatis</i> CIII<sub>2</sub>CIV<sub>2</sub> Supercomplex Binding, and In Vitro Antimycobacterial Activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets