Title: Underexplored chemical space as a source of novel compounds active against multidrug-resistant M. tuberculosis
Funder: Medical Research Council

Abstract: Rationale. The expanding threat of multidrug-resistant tuberculosis (MDR-TB) has prompted urgent calls for new approaches to tuberculosis (TB) control, including the implementation of new modes of drug-susceptibility testing and the use of alternative (shorter) therapeutic regimens aimed at expediting diagnosis and treatment. While such innovations are critical, the need for better anti-TB agents which can be applied as part of new combination therapies remains paramount: that is, the focus is squarely on TB drug development to deliver compounds (and regimens) with novel mechanisms of action (MOAs). The very early phases of preclinical development, though, continue to present the first major bottleneck in the TB drug discovery pipeline: a vanishingly small number of all molecules tested in primary screens advance to the next phase. Key recent scientific developments have profoundly informed the TB drug discovery process, and have resulted in a set of generally accepted criteria for the ideal preclinical candidate compound. However, there is growing recognition that current TB screening programmes are characterized by significant redundancy in the nature of the compounds screened (pharmaceutical libraries share huge numbers of identical or closely overlapping scaffolds, and the majority of identified “actives” are large, lipophilic compounds), as well as the mycobacterial targets identified. A lead compound for MDR-TB must satisfy at least three essential criteria: (i) it should possess a MOA distinct from existing anti-TB drugs; (ii) it should exhibit a pharmacological profile which suggests the capacity for good tissue penetration, with minimal liabilities in terms of host toxicity; and (iii) it should preferably act synergistically with – but at the very least should not antagonize – existing front- and second-line anti-TB agents. Each of these poses its own challenges from both a microbiological and a pharmacological perspective; however, it is critical they are addressed if new anti-TB drugs are to overcome the major obstacles to final approval for clinical use. Working Hypothesis. This proposal will attempt to satisfy these minimum criteria in proposing two separate but related projects which aim to explore the potential utility of distinct compound series comprising small, polar molecules with demonstrated anti-mycobacterial activity. Our contention is that, by matching a novel MOA with good physicochemical attributes, we can provide compelling lead compounds for optimization as to preclinical drug candidates within the allotted two-year timeframe. Study objective and specific aims. To repurpose a known cyclic hydroxamate (1) and a clinically used radiopharmaceutical metal complex (2) (in its non-radioactive form) as anti-mycobacterial agents with novel MOAs for development as lead compounds for MDR-TB. Our preliminary data suggest vitamin B6-dependent metabolism as the target of (1), which would represent a very exciting – and largely unexplored MOA – for MDR-TB, particularly given the synergy we observe with the known second-line agent, D-cycloserine. In contrast, the copper complex (2) constitutes a promising approach toward selective targeting of bacilli in hypoxic microenvironments considered important features of latent M. tuberculosis infection and active TB disease. Therefore, we propose a systemic programme of preliminary chemical, pharmacological, and microbiological analyses aimed at obtaining a definitive set of data to support an assessment of compound efficacy in vivo in an appropriate preclinical animal model(s) of TB. Expected outcomes. This project will explore two small molecules in parallel proof of concept studies aimed at testing the notio


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION