IN SILICO DETERMINATION OF POTENTIAL THERAPEUTIC TARGETS FOR LATENT PHASE Mycobacterium tuberculosis

LUCAS ALFREDO DEFELIPE; DARIO FERNANDEZ DO PORTO; PABLO IVAN PEREIRA RAMOS; MARISA FABIANA NICOLAS; LEANDRO RADUSKY; EZEQUIEL SOSA; ADRIAN GUSTAVO TURJANSKI; MARCELO ADRIÁN MARTÍ

Córdoba

Congreso; 11vo Congreso Argentino de Microbiología General; 2015

SAMIGE

Tuberculosis (TB) continues to be the most frequent cause of illness and death from an infectious agent globally despite currently available drug treatments. Moreover, no new drugs have been introduced and the combination of the first-line drugs remains necessary for a long time whiPetroch notably increases costs. Therefore, new drugs need to be developed, aiming to better treatment results, and to prevention of Multiple Drug Resistance (MDR) cases. Moreover, once inside the human host, Mycobacterium tuberculosis (Mtb), can remain alive for decades, hidden in the macrophagues facing nitrosative stress conditions. Reactive Nitrogen and Oxygen Species (RNOS) are known to present a concentration dependent mycobactericidal activity. Several new anti Mtb drugs are supposed to act by means of intracellular NO release, highlighting the relevance of RNOS for fighting the bacili and leading to the following idea: ?if we know which enzymes are targeted by RNOS to suppress or kill Mtb, we might be able to inhibit them with drugs impervious to TB nitrosative stress defenses.? Therefore, with this in mind,we performed an Mtb whole proteome wide analysis of potential nitrosative stress sensitive and relevant drug targets. To achieve this aim we combined a nitrosative stress sensitivity predicting method, which is based on our knowledge of chemical reactivity of RNOS towards proteins, with an analysis of each protein expression profile in stress conditions, essentiality anddruggability, in the context of Mtb metabolic network. Our results, which can be freely accessed at http://tuberq.proteinq.com.ar allowed us not only to identify several new potential Mtb drug targets, like I3PS or LipB expected to be critically sensitive under nitrosative stress conditions as those encountered in-vivo, but also to integrate and expand the knowledge for previous proposed targets. Moreover, the accessibility of the results and data surely represent an important tool for those researchers looking to new ways of killing Mtb.