Research Topics

We study how the human pathogen Mycobacterium tuberculosis adapts its metabolism and bioenergetic machinery during host infection to identify vulnerable pathways that can be exploited for drug discovery.

Amino acid metabolism of M. tuberculosis

We have recently discovered that methionine auxotrophy leads to rapid culture sterilization and avirulence in immunocompetent and immunocompromised mice. The most surprising aspects of that study were the inability of M. tuberculosis to scavenge methionine from the host and the rapid, persister-free eradication of bacilli. Methionine is part of the aspartate pathway in M. tuberculosis, which is a core anabolic pathway that provides the cell with the proteinogenic amino acids lysine, threonine, isoleucine and methionine, the peptidoglycan precursor diaminopimelate and S-adenosylmethionine, the main cofactor in cellular methyltransferase reactions. Sensing and regulating the abundance of these essential intermediates allows M. tuberculosis to integrate information from cell wall biosynthesis, translation and one carbon metabolism to maintain cellular homeostasis. Importantly, aspartate pathway homeostasis is linked to host metabolism, because the two precursors of the pathway, aspartate and glutamate, are scavenged from the host. We seek to understand the metabolic regulation of this complex, branched biosynthetic pathway and how the bacilli integrate intracellular and host metabolic information to maintain pathway homeostasis and persistence in vivo.

Bioenergetics of M. tuberculosis

The discovery of Bedaquiline (BDQ), a potent inhibitor of the mycobacterial F1Fo-ATP synthase, validated oxidative phosphorylation (OxPhos) as a viable drug target in Mtb. OxPhos is a ubiquitous metabolic pathway in which energy from nutrients is used to generate an electrochemical gradient, also called the proton motive force that drives the synthesis of ATP. OxPhos is required for the survival of both replicating and non-replicating (i.e. dormant) mycobacteria. Dissipation of the proton motive force leads to cell death. Therefore, drugs targeting enzymes involved in OxPhos are predicted to reduce duration of therapy as well as increase efficacy by killing actively replicating and dormant bacterial subpopulations.

We are interested in understanding the role of enzymes in the electron transport chain during host adaptation. Ability to produce ATP or shut off ATP production can have an impact on the bacilli’s ability to withstand host stress and antibiotic challenges.

Antibiotic persistence and drug mechanisms of metabolic interference

Antibiotic resistance, persistence and tolerance, are all important factors in the refractory behavior of M. tuberculosis during drug treatment. Very little is know on how and when M. tuberculosis enters one of these states. We investigate how drugs impact on M. tuberculosis metabolism and respiration and how metabolic adaptation allows the bacterium to become drug tolerant/persistent. Understanding what allows Mtb to persist and under which conditions they become resistant, is crucial information to develop shorter chemotherapy.