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
  • 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.

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