Tuberculosis (Edinburgh, Scotland) · 2021
A multi-targeting pre-clinical candidate against drug-resistant tuberculosis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Kaur Parvinder, Potluri Vijay, Ahuja Vijay Kamal, Naveenkumar C N, Krishnamurthy Ramya Vadageri, Gangadharaiah Shruthi Thimmalapura, Shivarudraiah Prasad, Eswaran Sumesh, Nirmal Christy Rosaline, Mahizhaveni Balasubramanian, Dusthackeer Azger, Mondal Rajesh, Batt Sarah M, Richardson Emily J, Loman Nicholas J, Besra Gurdyal Singh, Shandil Radha Krishan, Narayanan Shridhar
Аннотация
FNDR-20081 [4-{4-[5-(4-Isopropyl-phenyl)- [1,2,4]oxadiazol-3-ylmethyl]-piperazin-1-yl}-7-pyridin-3-yl-quinoline] is a novel, first in class anti-tubercular pre-clinical candidate against sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). In-vitro combination studies of FNDR-20081 with first- and second-line drugs exhibited no antagonism, suggesting its compatibility for developing new combination-regimens. FNDR-20081, which is non-toxic with no CYP3A4 liability, demonstrated exposure-dependent killing of replicating-Mtb, as well as the non-replicating-Mtb, and efficacy in a mouse model of infection. Whole genome sequencing (WGS) of FNDR-20081 resistant mutants revealed the identification of pleotropic targets: marR (Rv0678), a regulator of MmpL5, a transporter/efflux pump mechanism for drug resistance; and Rv3683, a putative metalloprotease potentially involved in peptidoglycan biosynthesis. In summary, FNDR-20081 is a promising first in class compound with the potential to form a new combination regimen for MDR-TB treatment.