TB is a chronic and complex disease caused by Mycobacterium tuberculosis (MTb), a bacterium that occurs in intra- and extracellular forms displaying widely different metabolic states. Traditionally, TB treatment entails the lengthy administration of drugs developed 60 years ago. However, the emergence of drug-resistant strains of MTb has led to the resurgence of TB in Europe. This emphasises the need for new drug development. To assist this drug discovery and development, scientists of the EU-funded MM4TB (More medicines for tuberculosis) project set out to identify new chemical entities that could serve as candidates for novel TB drugs. They followed a holistic approach starting from phenotypic screening of compounds in MTb-infected cells all the way to translation of the biological targets to synthetic drugs. More specifically, researchers employed cell-based approaches to find molecules with antibacterial activity in libraries of natural products or synthetic organic compounds. Using whole genome sequencing of resistant MTb mutants, they performed genetic and biochemical validation of the biological targets of the compounds. This information served as the basis for determining the structure of the targets and through facilitated medicinal chemistry for synthesising promising lead compounds for drugs. Overall, 10 new targets for drugs were identified and PBTZ169, the consortium's flagship candidate drug, successfully underwent preclinical development and entered clinical trials. Furthermore, the leads from two series of compounds targeting enzymes involved in MTb's central metabolism and cell wall synthesis were taken forward for synthesis. Collectively, the activities of the MM4TB study successfully addressed the imminent need for new drugs to combat TB. The deliverables of MM4TB and its EU-funded predecessor project NM4TB will be exploited by a not-for-profit foundation, Innovative Medicines for Tuberculosis (iM4TB), created under the current project.
Drugs, tuberculosis, MM4TB, PBTZ169, cell wall synthesis