Design and Development of Mycobacterium tuberculosis Lysine ɛ-Aminotransferase Inhibitors for Latent Tuberculosis Infection.
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.
Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, 500078, India.
Brindha Devi
BD
Parthiban
Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, 500078, India.
Shalini
S
Saxena
Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, 500078, India.
Manoj
M
Chandran
Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, 500078, India.
Padma Sridevi
PS
Jonnalagadda
Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, 500078, India.
Renu
R
Yadav
Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, 500078, India.
Rudraraju Reshma
RR
Srilakshmi
Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, 500078, India.
Yogeeswari
Y
Perumal
Centre for Infectious Disease Research, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, 500078, India.
Sriram
S
Dharmarajan
D000995:Antitubercular Agents / Q000737:chemistry* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D051306:L-Lysine 6-Transaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055985:Latent Tuberculosis / Q000188:drug therapy; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D051306:L-Lysine 6-Transaminase
Mycobacterium tuberculosis; Tuberculosis; antimycobacterial; lysine ɛ-aminotransferase