Foundation for Neglected Disease Research, Bangalore, India.
Foundation for Neglected Disease Research, Bangalore, India.
Tuberculosis (Edinb). 2021 Jul;129:102104. doi: 10.1016/j.tube.2021.102104. Epub 2021 Jun 18.
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.
FNDR-20081 [4-{4-[5-(4-异丙基苯基)-[1,2,4]恶二唑-3-基甲基]-哌嗪-1-基}-7-吡啶-3-喹啉]是一种新型的、针对敏感和耐药结核分枝杆菌（Mtb）的首创抗结核临床前候选药物。FNDR-20081 与一线和二线药物的体外联合研究显示没有拮抗作用，表明其与开发新的联合方案兼容。FNDR-20081 无细胞毒性且无 CYP3A4 风险，表现出对复制期 Mtb 的暴露依赖性杀伤作用，以及对非复制期 Mtb 的杀伤作用，并在感染小鼠模型中具有疗效。FNDR-20081 耐药突变体的全基因组测序（WGS）揭示了多种靶标的鉴定：marR（Rv0678），是 MmpL5 的调节剂，是一种用于药物耐药性的转运体/外排泵机制；和 Rv3683，一种可能参与肽聚糖生物合成的假定金属蛋白酶。总之，FNDR-20081 是一种很有前途的首创类化合物，有可能形成一种新的联合方案来治疗耐多药结核病。
