A multi-targeting pre-clinical candidate against drug-resistant tuberculosis
| Autor: | Shruthi Thimmalapura Gangadharaiah, Rajesh Mondal, C N Naveenkumar, Vijaykamal Ahuja, Radha Shandil, Shridhar Narayanan, Prasad Shivarudraiah, Gurdyal S. Besra, Sarah M. Batt, Azger Dusthackeer, Vijay Potluri, Balasubramanian Mahizhaveni, Christy Rosaline Nirmal, Emily J. Richardson, Parvinder Kaur, Sumesh Eswaran, Ramya Vadageri Krishnamurthy, Nicholas J. Loman |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Microbiology (medical) Tuberculosis THP-1 Cells 030106 microbiology Immunology Antitubercular Agents Drug Evaluation Preclinical Regulator Microbial Sensitivity Tests Drug resistance Biology Microbiology Mycobacterium tuberculosis Mice 03 medical and health sciences Drug Resistance Multiple Bacterial Tuberculosis Multidrug-Resistant medicine Animals Humans Whole genome sequencing Mice Inbred BALB C Molecular Structure CYP3A4 Transporter Hep G2 Cells medicine.disease biology.organism_classification 030104 developmental biology Infectious Diseases Quinolines Efflux |
| Zdroj: | Tuberculosis. 129:102104 |
| ISSN: | 1472-9792 |
| DOI: | 10.1016/j.tube.2021.102104 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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