Hit Generation in TB Drug Discovery: From Genome to Granuloma

Yuan, Tianao; Sampson, Nicole S.

doi:10.1021/acs.chemrev.7b00602

Cited by 89 publications

(114 citation statements)

References 259 publications

(576 reference statements)

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“…replicating vs non-replicating M. tuberculosis, or against multi-and extensively-drug resistant M. tuberculosis (M/XDR-TB) vs. classical strain. Moreover, despite the use of promising new drugs; such as bedaquiline which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid which inhibit mycolic acid synthesis as well as energy production [52,53]; there is an urgent need to discover new drugs to fight several mycobacterial infections such as Tuberculosis, Leprosis and Buruli Ulcer. The majority of drugs commercially available target a single molecule/process involved in the synthesis pathways essential for the bacterial survival during the infection process.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis

Nguyen

Martin

et al. 2018

Journal of Molecular Biology

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the virulence of associated mycobacterial species. CyC analogs. (A) The enzymatic activity of TesA was tested using pNP ester assay in the 4 presence of different concentrations of CyC7β, CyC8β, CyC17 and Orlistat as control. The 5 inhibitory effect was determined at the maximum rate of the reaction. Error bars represent the 6 standard deviation calculated from three independent experiments. Dose-response curves for 7 CyC7β, CyC8β, CyC17 and Orlistat were fitted in Kaleidagraph 4.2 Software (Synergy 8 Software). (B) Equal amounts of either TesA or TesA S104A were pre-treated with CyC17, 9 incubated with TAMRA-FP, separated by SDS-PAGE and visualized by Coomassie blue 10 staining (upper panel) or in-gel fluorescence visualization (middle panel). The merged image 11 is shown in the lower panel. TAMRA labelling of TesA is blocked by the covalent binding of 12 the CyC analogs to the catalytic Ser104 as evidenced with the TesA S104A variant. (C) 13 MALS/QELS/UV/RI analysis. The corresponding curve depicting the variation in UV 14 absorbance at 280 nm as a function of time (min. after sample injection in the High Performance 15 Liquid Chromatography system) for TesA (orange brown chromatogram) and TesA-CyC17 16 complex (grey chromatogram) have been superimposed and reported on the same 17 chromatogram. The traces indicating the molar mass (indicated on the left, in Da) are shown on 18 each peak by an arrow. Molecular masses of 31,800 Da (CV% <5%) for the monomer and 19 56,000 Da (CV% <4%) for the dimer have been calculated by the ASTRA software (Wyatt 20 Technology).

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Section: Discussionmentioning

confidence: 99%

Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis

Nguyen

Martin

et al. 2018

Journal of Molecular Biology

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“…PBTZ169 and BTZ043 show promising bactericidal activity against MDR‐TB strains. Both the drug candidates are very potent against replicating bacilli but show low activity against nonreplicating bacilli . PBTZ169 shows synergistic effects with bedaquiline .…”

Section: Pbtz169mentioning

confidence: 99%

“…Like other BTZs, PBTZ169 also targets DprE1 enzyme. PBTZ169 forms covalent adducts irreversibly with DprE1 . It is proposed that the nitro group of PBTZ169 undergoes reduction to form a nitroso derivative, which then covalently reacts with a cysteine residue of active site of DprE1 and forms an irreversible adduct which inhibits DprE1 .…”

Section: Pbtz169mentioning

confidence: 99%

“…PBTZ169 forms covalent adducts irreversibly with DprE1. 200 It is proposed that the nitro group of PBTZ169 undergoes reduction to form a nitroso derivative, which then covalently reacts with a cysteine residue of active site of DprE1 and forms an irreversible adduct which inhibits DprE1. 201 Inhibition of DprE1 interferes with the production of decaprenylphosphoryl arabinose, which is a key component for the synthesis of the mycobacterium cell wall arabinans.…”

Section: Mode Of Action Of Pbtz169mentioning

confidence: 99%

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An overview of new antitubercular drugs, drug candidates, and their targets

Bahuguna

Rawat

2019

Medicinal Research Reviews

131

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The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug‐resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four‐drug treatment regimen was introduced 40 years ago but the emergence of multidrug‐resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti‐TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug‐target interactions, and their structure‐activity relationship.

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“…Due to the large number of potential targets in the Mtb cholesterol metabolism pathway, it was not clear which protein target would be the most vulnerable to inhibition (14). Therefore, we undertook whole-cell phenotypic screening to identify inhibitors of Mtb growth.…”

Section: Introductionmentioning

confidence: 99%

The Mce3R Regulon Is Required for 6-Azasteroid Potentiation of Anti-TB Drug Activity

Yang¹,

Yuan²,

Ma³

et al. 2018

Preprint

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Mycobacterium tuberculosis (Mtb) infects humans and can live dormant within macrophages for decades, residing in a granuloma structure that arises from the host immune response and cholesterol is important for Mtb persistence in the host. Disruption of cholesterol-regulated genes results in reduced intracellular Mtb survival in animal models of infection. We phenotypically screened approximately 50 6-azasteroids against Mtb. We selected this steroid scaffold for its advantageous biophysical and pharmacokinetic properties. We found that at low micromolar concentrations a subset of 6-azasteroids sensitizes Mtb to the TB drug isoniazid and reduces the isoniazid MIC 15-30-fold. Two analogs selected for further study analogously sensitize Mtb to bedaquiline, and they improve the bactericidal activity of bedaquiline and isoniazid. Both 6-azasteroids improve the efficacy of isoniazid and bedaquiline under conditions of low oxygen, and demonstrate high synergy with bedaquiline (FIC index = 0.21, MIC BDQ = 16 nM at 1 µM 6-azasteroid). The rate of spontaneous resistance to 6-azasteroid is approximately 10 -7 and the 6-azasteroid resistance mutants retain their sensitivity to isoniazid and bedaquiline. Intriguingly, genes in the cholesterol-regulated Mce3R regulon are required for 6-azasteroid activity and genes in the cholesterol catabolism pathway are not. The Mce3R regulon has been implicated in stress resistance, and is not present in saprophytic strains of mycobacteria. We conclude that the Mce3R regulon encodes a cholesterol-dependent pathway important for pathogenesis that contributes to drug tolerance. Small molecule strategies to target the Mce3R regulon present an attractive avenue for further development of co-drugs that can improve existing tuberculosis chemotherapies. SIGNIFICANCEOne third of the world's population carries the infectious agent Mycobacterium tuberculosis (Mtb) that causes tuberculosis (TB), and every 17 seconds someone dies of TB worldwide. TB is the number one cause of death from a bacterial infectious disease. Current treatments require drug regimens of long duration to effectively cure TB disease and have many associated toxicities that are compounded by the high doses of long duration required. We have identified small molecules that increase Mtb susceptibility to existing TB drugs. The target of these small molecules is a pathway important for resistance of Mtb to stress. Development of a co-drug therapy has the potential to shorten treatment times and reduce toxicities associated with treatment of TB.

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Hit Generation in TB Drug Discovery: From Genome to Granuloma

Cited by 89 publications

References 259 publications

Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis

Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis

An overview of new antitubercular drugs, drug candidates, and their targets

The Mce3R Regulon Is Required for 6-Azasteroid Potentiation of Anti-TB Drug Activity

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