Attacking Mycobacterium Tuberculosis in the dormant phase: A Combination of expression data with structural druggability and nitrosative stress sensitivity

RADUSKY, LEANDRO G; DEFELIPE, LUCAS ALFREDO; TURJANSKI, ADRIAN GUSTAVO; MARTI, MARCELO ADRIÁN

Oro Verde

Congreso; 3 er Congreso Argentino de Bioinformática y Biología Computacional; 2012

Asociación Argentina de Bioinformática y Biología Computacional

It is estimated that one-third of the world population is infected with Mycobacterium tuberculosis (Mt), resulted in 1.8 million deaths worldwide. (World Health Organization, 2011) The host immune response to tuberculosis (TB) infection relies in phagocytosis of the bacilli by the macrophages resulting in the formation of a granuloma which stops bacterial replication. Inside the granuloma the bacteria faces a particular stressing condition characterized by hypoxia, inducible Nitric Oxide (NO) synthase derived NO and nutrient deprivation, and in response switches to a non replicative state, usually called the dormancy phase, where it can remain hidden and alive for decades. Reactivation of latent Mt is a high risk factor for disease development particularly in immunocompromised individuals. Common treatment of TB involves a long treatment with the front line drugs, isoniazid, rifampicin, pyrazinamide and ethambutol. However, the emergence of multi and extensively-drug-resistants (MDR and XDR) Mt strains, and the negative drugdrug interactions with certain HIV (or other disease) treatments, show the urgent need for new anti-TB drugs. In the present work we have performed a proteome scale analysis of Mt potential drug targets specific for the dormant phase. For this sake, for all Mt protein domains with available structure, we have first the determined their i) sensitivity to RNOS based upon aminoacidic composition of the active site, ii) pocket druggability using fpocket[1] and different pocket properties. This information was then combined with essentiality[2-4], off-target and microarray derived data [5] in a target prioritization pipeline. Using all the information cited above we performed a weighted search using Sensitivity of RNOS, Druggability, Essenciality, Offtargeting against Human targets and Upregulation in RNOS conditions as criteria for selection. Three new putative targets have been chosen to follow a virtual screening protocol. Acknowledgements This work was partially funded by ANPCyT PICT-2010-2805 awarded to AGT and Bunge y Born FBBEI9/10 (2011-2012) to MAM. LR is a ANPCyT Fellow. LAD is a CONICET Fellow. References 1. Schmidtke P et al (2010); J Med Chem. 53(15):5858-67 2. Sassetti C.M., et al (2003); PNAS 100 (22) 12989-12994 3. Rengarajan J, et al (2005); PNAS 102(23):8327-32 4. Sassetti C.M, et al (2003); Mol. Microbiol. 48(1), 77?84 5. Voskuil, M.I., et al. (2003); JEM 198 (5) 705-713