title: Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis.
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.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.
authors.forename: Srinivasa P S
authors.initials: SP
authors.lastname: Rao
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Ravinder R
authors.initials: RR
authors.lastname: Kondreddi
authors.forename: Maxime
authors.initials: M
authors.lastname: Herve
authors.forename: Luis R
authors.initials: LR
authors.lastname: Camacho
authors.forename: Pablo
authors.initials: P
authors.lastname: Bifani
authors.forename: Sarath K
authors.initials: SK
authors.lastname: Kalapala
authors.forename: Jan
authors.initials: J
authors.lastname: Jiricek
authors.forename: Ng L
authors.initials: NL
authors.lastname: Ma
authors.forename: Bee H
authors.initials: BH
authors.lastname: Tan
authors.forename: Seow H
authors.initials: SH
authors.lastname: Ng
authors.forename: Mahesh
authors.initials: M
authors.lastname: Nanjundappa
authors.forename: Sindhu
authors.initials: S
authors.lastname: Ravindran
authors.forename: Peck G
authors.initials: PG
authors.lastname: Seah
authors.forename: Pamela
authors.initials: P
authors.lastname: Thayalan
authors.forename: Siao H
authors.initials: SH
authors.lastname: Lim
authors.forename: Boon H
authors.initials: BH
authors.lastname: Lee
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.forename: Whitney S
authors.initials: WS
authors.lastname: Barnes
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.forename: Kevin
authors.initials: K
authors.lastname: Pethe
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: John
authors.initials: J
authors.lastname: Walker
authors.forename: Gu
authors.initials: G
authors.lastname: Feng
authors.forename: Sreehari
authors.initials: S
authors.lastname: Babu
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.forename: David
authors.initials: D
authors.lastname: Beer
authors.forename: Margaret
authors.initials: M
authors.lastname: Weaver
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.forename: Thomas
authors.initials: T
authors.lastname: Dick
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001682:Biological Availability; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007275:Injections, Intravenous; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D007211:Indoles; D026901:Membrane Transport Proteins