MepAnti · Exploiting the methylerythritol phosphate pathway as a source of drug targets for novel anti-infectives

Exploiting the methylerythritol phosphate pathway as a source of drug targets for novel anti-infectives

“Exploiting the methylerythritol phosphate pathway as a source of drug targets for novel anti-infectives” focuses on the anti-microbial resistance (AMR) problem. It is a unique network across Europe that combines leading scientists from academia and industry with the aim to train the next generation of scientists in the anti-infective drug-discovery field. Bacteria are expected to be the next global killer, but despite the awareness of the potential danger from AMR bacteria, few drug-makers have addressed this growing concern and very few new developments in antibiotic portfolios from pharmaceutical companies have been achieved. Therefore, common bacterial pathogens will continue to develop resistance to antibiotics. The MepAnti project aims to tackle this global problem by using underexplored targets that will afford compounds endowed with a novel mode of action (MoA). In fact, the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway is entirely absent in humans, while it is essential for medically relevant pathogens (e.g., Plasmodium falciparum, Mycobacterium tuberculosis, Escherichia coli, Pseudomonas aeruginosa and other Gram-negative bacteria). This pathway has been already validated as a potential source of novel anti-infective agents, but to date, only a few inhibitors have been reported. The current ITN program is organized into three different work packages (WP 1–3) that despite being thematically different, are complementary and overlap with each other. Specifically, WP 1 aims to elucidate the structural features of the constituent enzymes of the MEP pathway and to confirm the binding mode of inhibitors through complex crystal structures of inhibitors and proteins. The main objective of WP 2 is the design and synthesis of potent and selective inhibitors with concomitant multiparameter optimization. Subsequently, the compounds synthesized in WP 2 will be tested and further validated in relevant pathogens in WP 3. This collaborative network with an intersectoral composition will enable the identification of new promising compounds to combat the global problem of emerging resistance. To conclude, the project has achieved several significant outcomes: - High-resolution structures were solved for key MEP pathway enzymes from pathogenic organisms. This enabled the identification of unique binding sites for selective inhibition. - Design and synthesis of multiple novel inhibitors with promising in vitro activity against pathogens. The best candidates showed potential for further development. - Mechanistic studies have revealed innovative modes of action, such as irreversible inhibition, enhancing the compounds' potential for therapeutic application. Besides the scientific advancements, MepAnti has equipped the next generation of researchers with multidisciplinary skills in structural biology, medicinal chemistry, and microbiology. As a next step, the identified inhibitors will be further optimized relative to potency, selectivity, and pharmacokinetics, to ultimately develop clinical candidates.

Data: CORDIS, © European Union