학술논문
Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis.
Document Type
Academic Journal
Author
Rao SP; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Lakshminarayana SB; Kondreddi RR; Herve M; Camacho LR; Bifani P; Kalapala SK; Jiricek J; Ma NL; Tan BH; Ng SH; Nanjundappa M; Ravindran S; Seah PG; Thayalan P; Lim SH; Lee BH; Goh A; Barnes WS; Chen Z; Gagaring K; Chatterjee AK; Pethe K; Kuhen K; Walker J; Feng G; Babu S; Zhang L; Blasco F; Beer D; Weaver M; Dartois V; Glynne R; Dick T; Smith PW; Diagana TT; Manjunatha UH
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
Subject
Language
English
Abstract
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.