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Design and Development of Mycobacterium tuberculosis Lysine ɛ ‐Aminotransferase Inhibitors for Latent Tuberculosis Infection
Author(s) -
Parthiban Brindha Devi,
Saxena Shalini,
Chandran Manoj,
Jonnalagadda Padma Sridevi,
Yadav Renu,
Srilakshmi Rudraraju Reshma,
Perumal Yogeeswari,
Dharmarajan Sriram
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12655
Subject(s) - mycobacterium tuberculosis , tuberculosis , latent tuberculosis , microbiology and biotechnology , lysine , biology , virology , medicine , chemistry , biochemistry , pathology , amino acid
Lysine ɛ ‐aminotransferase ( LAT ) is a protein involved in lysine catabolism, and it plays a significant role during the persistent/latent phase of Mycobacterium tuberculosis ( MTB ), as observed by its up‐regulation by ~40‐fold during this stage. We have used the crystal structure of MTB LAT in external aldimine form in complex with its substrate lysine as a template to design and identify seven lead compounds with IC 50 ranging from 18.06 to > 90 μ m . We have synthesized 21 compounds based on the identified lead, and compound 21 [2,2′‐oxybis( N ′‐(4‐fluorobenzylidene)acetohydrazide)] was found to be the most active with MTB LAT IC 50 of 0.81 ± 0.03 μ m . Compound 21 also showed a 2.3 log reduction in the nutrient‐starved MTB model and was more potent than standard isoniazid and rifampicin at the same dose level of 10 μ g/mL.