title: Identification of a small molecule with activity against drug-resistant and persistent tuberculosis.
abstract: A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Dhinakaran
authors.initials: D
authors.lastname: Sambandan
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Halder
authors.forename: Jianing
authors.initials: J
authors.lastname: Wang
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Batt
authors.forename: Brian
authors.initials: B
authors.lastname: Weinrick
authors.forename: Insha
authors.initials: I
authors.lastname: Ahmad
authors.forename: Pengyu
authors.initials: P
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Kim
authors.forename: Morad
authors.initials: M
authors.lastname: Hassani
authors.forename: Stanislav
authors.initials: S
authors.lastname: Huszar
authors.forename: Claudia
authors.initials: C
authors.lastname: Trefzer
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
authors.forename: Takushi
authors.initials: T
authors.lastname: Kaneko
authors.forename: Khisi E
authors.initials: KE
authors.lastname: Mdluli
authors.forename: Scott
authors.initials: S
authors.lastname: Franzblau
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.forename: Kai
authors.initials: K
authors.lastname: Johnsson
authors.forename: Kai
authors.initials: K
authors.lastname: Johnson
authors.forename: Katarina
authors.initials: K
authors.lastname: Mikusova
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Klaus
authors.initials: K
authors.lastname: Fütterer
authors.forename: Scott H
authors.initials: SH
authors.lastname: Robbins
authors.forename: S Whitney
authors.initials: SW
authors.lastname: Barnes
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D000429:Alcohol Oxidoreductases; D000595:Amino Acid Sequence; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial; D005260:Female; D005798:Genes, Bacterial; D057166:High-Throughput Screening Assays; D007538:Isoniazid / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D012293:Rifampin / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D052160:Benzothiazoles; C583624:TCA1 compound; D013876:Thiophenes; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis; D002238:Carbohydrate Epimerases; D007538:Isoniazid; D012293:Rifampin
keywords: drug resistance; dual mechanism