title: Novel inhibitors of InhA efficiently kill Mycobacterium tuberculosis under aerobic and anaerobic conditions.
abstract: Drug resistance in Mycobacterium tuberculosis has become a serious global health threat, which is now complicated by the emergence of extensively drug-resistant strains. New drugs that are active against drug-resistant tuberculosis (TB) are needed. We chose to search for new inhibitors of the enoyl-acyl carrier protein (ACP) reductase InhA, the target of the first-line TB drug isoniazid (also known as isonicotinoic acid hydrazide [INH]). A subset of a chemical library, composed of 300 compounds inhibiting Plasmodium falciparum enoyl reductase, was tested against M. tuberculosis. Four compounds were found to inhibit M. tuberculosis growth with MICs ranging from 1 μM to 10 μM. Testing of these compounds against M. tuberculosis in vitro revealed that only two compounds (CD39 and CD117) were bactericidal against drug-susceptible and drug-resistant M. tuberculosis. These two compounds were also bactericidal against M. tuberculosis incubated under anaerobic conditions. Furthermore, CD39 and CD117 exhibited increased bactericidal activity when used in combination with INH or rifampin, but CD39 was shown to be toxic to eukaryotic cells. The compounds inhibit InhA as well the fatty acid synthase type I, and CD117 was found to also inhibit tuberculostearic acid synthesis. This study provides the TB drug development community with two chemical scaffolds that are suitable for structure-activity relationship study to improve on their cytotoxicities and bactericidal activities in vitro and in vivo.
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilchèze
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Baughn
authors.forename: JoAnn
authors.initials: J
authors.lastname: Tufariello
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Leung
authors.forename: Mack
authors.initials: M
authors.lastname: Kuo
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
authors.forename: David
authors.initials: D
authors.lastname: Alland
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
mesh_terms: D000332:Aerobiosis; D000693:Anaerobiosis; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D013229:Stearic Acids / Q000378:metabolism; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D013229:Stearic Acids; C026082:tuberculostearic acid; D010088:Oxidoreductases; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; C085257:InhA protein, Mycobacterium; D054890:Fatty Acid Synthase, Type I