M. tuberculosis 16kDa, 38 kDa

A series ofMycobacterium tuberculosisTMPK (MtbTMPK) inhibitors based on a reported compound3were synthesized and evaluated for their capacity to inhibitMtbTMPK catalytic activity and the growth of a virulentM. tuberculosisstrain (H37Rv). Modifications of the scaffold of3failed to afford substantial improvements inMtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of3resulted in compound21jwith improvedMtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of21jto thepara-position afforded isomer21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 mu M).

Tuberculosis (TB), an infectious disease caused byMycobacterium tuberculosis, is among the top 10 leading causes of death worldwide. The treatment course for TB is challenging; it requires antibiotic administration for at least 6 months, and bacterial drug resistance makes treatment even more difficult. Understanding the mechanisms of resistance is important for improving treatment. To investigate new mechanisms of isoniazid (INH) resistance, we obtained three INH-resistant (INH-R)M. tuberculosisclinical isolates collected by the Taiwan Centers for Disease Control (TCDC) and sequenced genes known to harbor INH resistance-conferring mutations. Then, the relationship between the mutations and INH resistance of these three INH-R isolates was investigated. Sequencing of the INH-R isolates identified three novelkatGmutations resulting in R146P, W341R, and L398P KatG proteins, respectively. To investigate the correlation between the observed INH-R phenotypes of the clinical isolates and thesekatGmutations, wild-typekatGfrom H37Rv was expressed on a plasmid (pMN437-katG) in the isolates, and their susceptibilities to INH were determined. The plasmid expressing H37RvkatGrestored INH susceptibility in the two INH-R isolates encoding the W341R KatG and L398P KatG proteins. In contrast, no phenotypic change was observed in the KatG R146P isolate harboring pMN437-katG. H37Rv isogenic mutant with W341R KatG or L398P KatG was further generated. Both showed resistant to INH. In conclusion, W341R KatG and L398P KatG conferred resistance to INH inM. tuberculosis, whereas R146P KatG did not affect the INH susceptibility ofM. tuberculosis.