Project Portugal 2030

Summary

TB claims the lives of more than 1 million people per year. According to the World Health Organization End TB strategy, shorter treatment regimens is key to eradicate TB, which requires the development of new drugs. FOLCURE-TB aligns with this strategy by exploiting Mtb folate cycle vulnerability in lipid-rich environments to sterilize infection and opening the path for the discovery of new anti-TB drugs. Classically, antimicrobial development focus on the inhibition of specific metabolic pathways/ cell processes of the pathogen. The main innovation of the FOLCURE-TB approach is the identification of potential drug targets that allow for a dual effect: 1) inhibition of an essential metabolic pathway on the pathogen (folate cycle) and 2) potentiation of host LC-FFA antibacterial activity. To accomplish this, FOLCURE-TB approach is divided in 5 specific aims: Aim 1. To understand the mechanism of Mtb GlyA1 and ThyA vulnerability in the presence of LC-FFA. Targeted and unbiased metabolomics approaches will be applied to identify differential accumulation of metabolites that can explain the vulnerability of the folate cycle enzymes GlyA1 and ThyA in the presence of LC-FFA. Beyond advancement on the knowledge of an important pathogen’s adaptation to the host, we expect to identify new metabolic vulnerabilities (see task 1). Aim 2. To assess the essentiality of Mtb GlyA1 and ThyA during infection. Essentiality will be determined through infection of C3HeB/FeJ mice with Mtb strains, a model that both mimics the human blood signature of TB [12], [13] and allows generation of caseating granulomas [17]. These experiments are expected to validate GlyA1 and ThyA as stand-alone drug targets (see task 2). Aim 3. To identify metabolic interactions with GlyA1 and ThyA impairment in Mtb. CRISPRi libraries [14] will be used to identify genetic interactions with glyA1 and thyA in the presence of LC-FFA. Identification of antagonistic and synergistic effects will provide valuable information for a future integration of GlyA1 and ThyA inhibitors in combinatorial drug treatment regimen (see task 3). Aim 4. To identify chemical backbones for the development of Mtb GlyA1 and ThyA inhibitors. Mtb GlyA1 and ThyA homologues in humans are drug targets for anticancer drugs. We will test if these compounds are active against Mtb through the inhibition of GlyA1 and ThyA. Compounds active against Mtb will be good candidates for further optimization into new antifolates for TB treatment (see task 4). Aim 5: To implement the strategy of valuation, dissemination, and communication of outcomes. From the different activities in the plan, we can highlight the organization of a round table and a final symposium. The roundtable will account with representants of the different identified stakeholders, thus engaging a wider audience. The final symposium will be more directed to a scientific audience and will discuss future directions of this line of research. We also increase the competences of team members in knowledge transfer and established a collaboration that opens the path to drug development (see task 5). In all FOLCURE-TB has the objective to contribute with concrete solutions to a disease that remains a serious threat to global health.