2. Academic Validation
  3. Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis

Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis

  • Sci Transl Med. 2013 Dec 4;5(214):214ra168. doi: 10.1126/scitranslmed.3007355.
Srinivasa P S Rao 1,  Suresh B Lakshminarayana,  Ravinder R Kondreddi,  Maxime Herve,  Luis R Camacho,  Pablo Bifani,  Sarath K Kalapala,  Jan Jiricek,  Ng L Ma,  Bee H Tan,  Seow H Ng,  Mahesh Nanjundappa,  Sindhu Ravindran,  Peck G Seah,  Pamela Thayalan,  Siao H Lim,  Boon H Lee,  Anne Goh,  Whitney S Barnes,  Zhong Chen,  Kerstin Gagaring,  Arnab K Chatterjee,  Kevin Pethe,  Kelli Kuhen,  John Walker,  Gu Feng,  Sreehari Babu,  Lijun Zhang,  Francesca Blasco,  David Beer,  Margaret Weaver,  Veronique Dartois,  Richard Glynne,  Thomas Dick,  Paul W Smith,  Thierry T Diagana,  Ujjini H Manjunatha
Affiliations

Affiliation

  • 1 Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.
PMID: 24307692 DOI: 10.1126/scitranslmed.3007355
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.

Figures
Products