The research interest
of the team is focused on the strategies that pathogens use to attack and
exploit hosts, and how hosts defend themselves against those attacks. A primary
goal of the laboratory is to understand how bacteria adapt their metabolism and
energy production mechanisms to exploit the nutritional resources of the host
for growth and persistence. We believe that an in-depth understanding of the
bacterial metabolic circuits, required to establish infection in vivo, is also
a requirement for the development of innovative strategies to control disease
progression.
We are also
interested in characterising metabolic synthetic lethal genetic interactions in
bacteria. Several new lines of evidence suggest that a combination of weakly
active chemical entities can result in a potent synergistic drug combination
against multidrug resistant bacteria, revealing the existence of numerous
synthetic-lethal genetic interactions. We are using a chemical genomics
approach to decipher how a slight perturbation of multiple metabolic pathways
can lead to a collapse of an entire biological system and to exploit this
knowledge to develop novel antibacterial drug combinations.
A related interest of
the lab is to study the system-level perturbation induced by antibiotics.
Recent findings suggest that antibiotic-induced cell death is not directly
linked to the inhibition of the primary target but to a collapse of central
metabolism. We thus seek to elucidate the mechanisms behind antibacterial
induced cell-death using a multidisciplinary approach combining functional
genomics, chemical biology, genetics and biochemistry.
Selected Publications
Kalia NP,
Hasenoehrl EJ, ... Pethe K. (2017). Exploiting the synthetic lethality betweenterminal respiratory oxidases to kill M. tuberculosis and clear host infection. Proceedings of the National Academy
of Sciences. 114(28):7426-31.
Murima P,
Zimmermann M, ... Pethe K, et al. (2016). A rheostat mechanism governs the bifurcation of carbonflux in mycobacteria. Nature
Communications. 7:12527.
Pethe K, Bifani P,
Jang J, et al. (2013). Discovery of Q203, a potent clinical candidate for the
treatment of tuberculosis. Nature
Medicine. 19(9);1157-60.
Mak PA, Srinivasa
PSR, ... Pethe K, et al. (2012). A high throughput screen to identify inhibitors of ATP homeostasis innon-replicating Mycobacterium tuberculosis. ACS Chemical Biology. 7(7);1190-7.
Pethe K,
Sequeira PC, Agarwalla S, et al. (2010). A chemical genetic screen inMycobacterium tuberculosis identifies carbon-source dependent growth inhibitorsdevoid of in vivo efficacy. Nature
Communications. 1:57.
Rao SP,
Alonso S, ... Pethe K. (2008). The protonmotive force is required formaintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proceedings
of the National Academy of Sciences. 105(33);11945-50.
Pethe K,
Swenson DL, Alonso S, et al. (2004). Isolation of Mycobacterium tuberculosis mutants defective in the arrest of phagosomematuration. Proceedings of the
National Academy of Sciences of the United States of America, 101(37),
13642-7.
Temmerman S,
Pethe K, Alonso S, et al. (2004). Methylation-dependent Tcell immunity to Mycobacterium tuberculosis heparin-binding hemagglutinin. Nature Medicine. 10(9);935-41.
Pethe K,
Bifani P, Drobecq H, et al. (2002). Mycobacterial heparin-binding hemagglutinin and laminin-binding protein shareantigenic methyllysines that confer resistance to proteolysis. Proceedings of the National Academy of
Sciences. 99(16);10759-64.
Pethe K, Alonso
S, Biet F, et al. (2001). The mycobacterialheparin-binding haemagglutinin adhesion is required for extrapulmonarydissemination. Nature. 412(6843);190-4.