title: Identification of compounds with potential antibacterial activity against Mycobacterium through structure-based drug screening.
abstract: To identify novel antibiotics against Mycobacterium tuberculosis, we performed a hierarchical structure-based drug screening (SBDS) targeting the enoyl-acyl carrier protein reductase (InhA) with a compound library of 154,118 chemicals. We then evaluated whether the candidate hit compounds exhibited inhibitory effects on the growth of two model mycobacterial strains: Mycobacterium smegmatis and Mycobacterium vanbaalenii. Two compounds (KE3 and KE4) showed potent inhibitory effects against both model mycobacterial strains. In addition, we rescreened KE4 analogs, which were identified from a compound library of 461,383 chemicals through fingerprint analysis and genetic algorithm-based docking simulations. All of the KE4 analogs (KES1-KES5) exhibited inhibitory effects on the growth of M. smegmatis and/or M. vanbaalenii. Based on the predicted binding modes, we probed the structure-activity relationships of KE4 and its analogs and found a correlative relationship between the IC50 values and the interaction residues/LogP values. The most potent inhibitor, compound KES4, strongly and stably inhibited the long-term growth of the model bacteria and showed higher inhibitory effects (IC50 = 4.8 μM) than isoniazid (IC50 = 5.4 μM), which is a first-line drug for tuberculosis therapy. Moreover, compound KES4 did not exhibit any toxic effects that impede cell growth in several mammalian cell lines and enterobacteria. The structural and experimental information of these novel chemical compounds will likely be useful for the development of new anti-TB drugs. Furthermore, the methodology that was used for the identification of the effective chemical compound is also likely to be effective in the SBDS of other candidate medicinal drugs.
authors.affiliation: Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka-shi, Fukuoka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kinjo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Koseki
authors.forename: Maiko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yamada
authors.forename: Koji
authors.initials: K
authors.lastname: Morita
authors.forename: Kento
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Ryoya
authors.initials: R
authors.lastname: Tsurusawa
authors.forename: Gulcin
authors.initials: G
authors.lastname: Gulten
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Komatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kitamura
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Aoki
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007928:Lethal Dose 50; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium