title: Discovery of novel lysine ɛ-aminotransferase inhibitors: An intriguing potential target for latent tuberculosis.
abstract: Mycobacterium tuberculosis (MTB) has remarkable ability to persist in the human host and causes latent infection in one third of the world population. Currently available tuberculosis (TB) drugs while effective in killing actively growing MTB, is largely ineffective in killing persistent or latent MTB. Lysine-ɛ aminotransferase (LAT) enzyme is reported to be highly up-regulated (41.86 times) in in vitro models of TB designed to mimic the latent stage. Hence inhibition of this MTB LAT seems attractive for developing novel drugs against latent TB. In the present study, crystal structure of the MTB LAT bound to substrate was used as a framework for structure-based design utilizing database compounds to identify novel thiazole derivative as LAT inhibitors. Thirty six compounds were synthesized and evaluated in vitro for their ability to inhibit LAT, in vitro activity against latent MTB, in vivo activity using Mycobacterium marinum infected zebra fish and cytotoxicity as steps toward the derivation of structure-activity relationship (SAR) for lead optimization. Compound 4-methoxy-2-(pyridin-4-yl)thiazole-5-carboxylic acid (24) emerged as the most promising lead with an IC50 of 1.22 ± 0.85 μM against LAT and showed 2.8 log reduction against nutrient starved MTB, with little cytotoxicity at a higher concentration (>50 μM). It also exhibited 1.5 log reduction of M. marinum load in in vivo zebra fish model at 10 mg/kg.
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors: Parthiban Brindha
authors: PB
authors: Devi
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors: Jonnalagadda Padma
authors: JP
authors: Sridevi
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors: Shruti Singh
authors: SS
authors: Kakan
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors: Shalini
authors: S
authors: Saxena
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors: Variam Ullas
authors: VU
authors: Jeankumar
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors: Vijay
authors: V
authors: Soni
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors: Hasitha Shilpa
authors: HS
authors: Anantaraju
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors: Perumal
authors: P
authors: Yogeeswari
authors: Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors: Dharmarajan
authors: D
authors: Sriram
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D051306:L-Lysine 6-Transaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055985:Latent Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D050296:Microbial Viability / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009165:Mycobacterium Infections, Nontuberculous / Q000188:drug therapy / Q000382:microbiology; D019910:Mycobacterium marinum / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013329:Structure-Activity Relationship; D013997:Time Factors; D015027:Zebrafish
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D051306:L-Lysine 6-Transaminase
keywords: Latent tuberculosis; Lysine ɛ-aminotransferase; Mycobacterium tuberculosis; Zebra fish M. marinum model