(200f) Pump-Down the Mycobacterium Tuberculosis: A DNA Gyrase/P-Glycoprotein Combined Inhibition Approach

Tuberculosis (TB) is one of the most common infectious diseases worldwide, with about one third of world population infected with Mycobacterium tuberculosis (M.Tb.). More frightening is the recent emergence of multidrug and extensively drug resistant M.Tb. strains (MDRM.Tb. and XDRM. Tb., respectively). In the setting of drug resistance or intolerance to firstline agents (e.g. isoniazid, rifampicin…), secondline agents may be used. Indeed, fluoroquinolones have been classified as secondline antituberculous drugs since they are active on isolated M. Tb. expressing resistance to both isoniazid and rifampicin. Recently we synthesized a new series of quinolones derivatives, endowed with a good antimycobacterial activity (against H37Rv and H37Ra and further clinical isolates of MDRTB/ XDRTB strains) coupled with low cytotoxicity. In this work we present a combined in vitro/in silico approach with the aim (i) to improve knowledge on the structure-activity relationship (SAR) of the new compounds, (ii) to identify a pharmacophoric map and (iii) enhance the biological activity against the biological target. According to the computational results, new derivatives will be designed and synthesized to obtain compounds able to inhibit replication in H37Rv and clinically isolated M.Tb. strains. The identification of a new action mechanism by our derivatives compared to classical quinolones could be used to generate a new class of drugs, with the aim to create an innovative treatment plan able to reduce possible pharmacological resistances. In parallel a series of new quinoxaline derivatives, previously identified as Pglycoprotein (Pgp) inhibitors, will be investigate on M.Tb. strains, in combination with new compounds and classical drugs. In fact, efflux pump inhibitors could enhance a latent biological activity and implement the DNAgyrase inhibitors activity against resistant M. Tb. strains. Even in this topic the computational and the experimental tecniques will be applied in order to improve the level of knowledge on the mechanism of action of these molecules againt their biological target. All obtained data will be analyzed and promising compounds will be optimized to obtain selected gold compounds.