New enzyme-targeted drug program aims at drug-resistant tuberculosis

Tuberculosis remains a major public health challenge because of a rising number of multi-drug-resistant cases and an increase in deaths. Meeting the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030 requires new treatments, and researchers are urgently pursuing fresh approaches. In this report led by Laura A. T. Cleghorn, scientists review a focused medicinal chemistry effort aimed at a specific bacterial enzyme: the Mycobacterium tuberculosis lysyl-tRNA synthetase (LysRS). The team had previously reported the discovery of 49, a pre-clinical candidate that acted through inhibition of LysRS. Building on that initial finding, the group carried out a full program to move from an original hit compound to an optimised lead suitable for further testing. The work concentrated on understanding how to block the bacterial enzyme that is essential for protein production in the pathogen and on turning that biochemical insight into compounds with the right properties to become drugs. This review summarizes the stepwise chemical design and development that took the project from a promising molecule toward candidates ready for laboratory and animal evaluation.

The key methodological advance reported in this work was the integration of structural biology with medicinal chemistry. The program was guided by the first crystal structure of M. tuberculosis LysRS, which provided a detailed map of the enzyme’s shape and helped chemists design molecules that fit and block it. Starting from an initial hit, the team ran a full medicinal chemistry program to refine molecular features, iterating designs to improve how the molecules behave in the body. They paid particular attention to the physicochemical and pharmacokinetic properties of the compounds — in other words, how the molecules absorb, distribute, metabolize and persist — and modified chemical structures to reach an optimised lead. The end products of this optimisation were compounds described as suitable for evaluation in mouse efficacy models of tuberculosis and as having the potential for clinical development. Throughout, the work preserved the mechanism of action first seen with 49 and used the crystal structure of M. tuberculosis LysRS to inform each design step.

The significance of this work lies in advancing a targeted route toward new tuberculosis treatments that act on LysRS. By moving from a hit through a disciplined optimisation process — and by leveraging the first crystal structure of M. tuberculosis LysRS — the researchers have generated optimised leads with properties suitable for animal testing and possible clinical progression. That matters because current drug-resistant forms of tuberculosis demand fresh classes of drugs that work by new mechanisms. Compounds that inhibit LysRS, exemplified by the earlier-discovered 49 and the optimised leads reviewed here, provide a concrete starting point for such new therapies. While further testing in mouse efficacy models and subsequent clinical development will be required, this medicinal chemistry program represents a clear step toward addressing the urgent need for novel tuberculosis medicines and supports broader efforts to meet the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030.