Energy Metabolism Inhibitors

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The length of current TB regimens is based largely on the need to eradicate the slow-growing, dormant populations of M.tb. However, even dormant bacteria need energy to live. Drugs that target the energy-generation process should be good candidates for shortening TB therapy.

Ruthenium (II) phosphine/diimine/picolinate complexes

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Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated

Menaquinone Synthase Inhibitors

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The specific aims for the initial 18 months of this proof of concept program are as follows: In vivo target validation by genetic deletion of MenA; Relate the ability of the lead compounds to kill M.tb to their ability to inhibit the presumed target, MenA; Medicinal chemistry improvement of the lead series and selection of a compound suitable for a pharmacologic proof-of-concept in the mouse; and In vivo pharmacologic proof of concept.

Malate Synthase Inhibitors

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The malate synthase project began in 2007. High throughput screening has been completed with a 1.4 million compound library and hits have been identified. Screening hits were validated and characterized with dose-response curves against the enzyme and Mtb whole cells. Interactions with the enzyme have been determined on atomic level through crystals structures of malate synthase-inhibitor complexes. From rounds of structure-based design, chemical synthesis and testing of analogs three chemically distinct series of inhibitors emerged.

Whole-Cell Hit-to-Lead

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A target-based approach for antibacterial drug discovery (for example, inhibition of a particular enzyme) is one potential strategy toward drug development. A complimentary approach that screens for compounds that inhibit the growth of the organism of interest or a model organism, without any bias toward a particular target, can also be pursued. This program utilizes such an approach. A portion of this work has been published (L. Ballell, et al., ChemMedChem. 2013, 8, 313). Screening of newly acquired compounds against Mtb is continuing.

GyrB Inhibitors

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A high throughput assay that measures the activity of mycobacterial topoisomerase was developed and used to screen AstraZeneca’s corporate compound collection. Following hit evaluation a number of scaffolds were identified and hit-to-lead work completed. Activity in the mouse model of acute infection (proof-of-concept) was demonstrated, after which the active compounds would provide the lead compound(s) for an optimization effort.

Telacebec (Q203)

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February 2022. Publication. Hards, Kiel et al. “An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.” Communications Biology vol. 5,1 166. PMCID: PMC8873251

AZD5847

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February 25, 2016: AstraZeneca has removed AZD-5847 from development. https://www.astrazeneca.com/our-science/pipeline.html The Phase 2 EBA trial has been completed but not yet published. The initial objectives of the project were: 1. To assess the safety and tolerability of AZD5847 after receiving oral doses on a single day (Part A) or after receiving a single oral dose in two periods (Part B). For volunteers in Part B, the effect of food on the PK of AZD5847 will also be studied.

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