Design and Development of Mycobacterium tuberculosis Lysine ɛ-Aminotransferase Inhibitors for Latent Tuberculosis Infection

Chemical Biology & Drug Design
Brindha Devi ParthibanSriram Dharmarajan

Abstract

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 IC50 ranging from 18.06 to > 90 μm. 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 IC50 of 0.81 ± 0.03 μm. 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 μg/mL.

References

Sep 7, 2001·Annual Review of Microbiology·L G Wayne, C D Sohaskey
Feb 24, 2004·Frontiers in Bioscience : a Journal and Virtual Library·Ying Zhang
Mar 24, 2004·Nature Reviews. Microbiology·Graham R StewartDouglas B Young
Mar 14, 2007·Inflammation & Allergy Drug Targets·Pere-Joan Cardona

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