Marco da Silva

The human pathogen Mycobacterium tuberculosis (Mtb) thrives in lipid-rich microenvironments. A strong body of evidence demonstrated that, during infection, Mtb utilizes long-chain fatty acids (LCFA) as a preferred carbon source. However, LCFA also have antimicrobial properties. Mtb must therefore employ mechanisms to utilize LCFA while mitigating their toxicity. Using transposon sequencing (TnSeq), we defined the Mtb LCFA resistome as comprising 38 genes. Surprisingly, LCFA resistance requires diverse metabolic pathways, indicating pleiotropic effects of LCFA on Mtb physiology. We investigated the function of the TnSeq top-hit, the universal stress protein TB15.3, and demonstrate that it participates in a “metabolic brake” mechanism restricting LCFA uptake and catabolism to prevent membrane hyperpolarization. TB15.3 absence caused Mtb to lose viability during chronic infection in mice and in an in vitro caseum model. Our work highlights Mtb LCFA resistance mechanisms as an important host adaptation and a promising target space for drug development.

Toxoplasmosis is a parasitic disease caused by the globally distributed protozoan parasite Toxoplasma gondii, which infects around one-third of the world population. This disease may result in serious complications for fetuses, newborns, and immunocompromised individuals. Current treatment options are old, limited, and possess toxic side effects. Long treatment durations are required since the current therapeutic system lacks efficiency against T. gondii tissue cysts, promoting the establishment of latent infection. This review highlights the most promising drug targets involved in anti-T. gondii drug discovery, including the mitochondrial electron transport chain, microneme secretion pathway, type II fatty acid synthesis, DNA synthesis and replication and, DNA expression as well as others. A description of some of the most promising compounds demonstrating antiparasitic activity, developed over the last decade through drug discovery and drug repurposing, is provided as a means of giving new perspectives for future research in this field.