In vitro bactericidal activities of two novel dihydropyridine derivatives against Mycobacterium tuberculosis.

INTRODUCTION: Introducing new and effective antitubercular agents is important in tuberculosis control programs. In this study, the in vitro antitubercular activity of two novel 1,4-dihydropyridine derivatives (F-27, Cl-33) were screened against a total of 113 different strains of Mycobacterium tuberculosis (77 susceptible and 36 resistant clinical isolates). METHODOLOGY: The in vitro activities of these compounds were evaluated based on the modified broth macro-dilution assay. RESULTS: Compound F-27 showed more than 90% growth inhibition at the range of 2 to 8 µg/mL (minimum inhibitory concentration [MIC]90: 4.13 ± 0.45 µg/mL; p  < 0.01), and complete growth inhibition was observed at the range of 8 to 32 µg/mL (minimum bactericidal concentration [MBC]: 11.2 ± 1.65 µg/mL; p < 0.01) against susceptible strains. However, 92% of the resistant strains showed some degree of susceptibility against this compound (MIC90 range: 16 to 64 µg/mL; mean: 40.4 ± 8 µg/mL; p < 0.01). It was found that although there is a linear relationship between the inhibitory activity of F-27 and isoniazid against resistant strains at low concentrations (r = 0.484, p < 0.001), there was no relationship between resistance to isoniazid and F-27 at higher concentrations (r = 0.019, p > 0.1). This may emphasize no cross-resistance between F-27 and isoniazid. CONCLUSIONS: Considering the sufficient sample size of the study and based on the excellent antimycobacterial activity of F-27, it could be concluded that F-27 is a potent candidate as a lead compound, and may be considered for development of a new antitubercular agent.

Screening of the antimycobacterial activity of novel lipophilic agents by the modified broth based method.

Most of the introduced susceptibility methods of Mycobacterium tuberculosis have some disadvantages for screening. Therefore, the selection of susceptibility assay for evaluating candidate agents must be determined case by case. In this study, we evaluated the validity of a modified broth dilution-based assay in comparison to the gold standard proportional method for microbial sensitivity test of new lipophilic compounds candidate as antitubercular agents. The in-vitro susceptibilities of 114 M. tuberculosis strains were separately tested against isoniazid and two lipophilic antitubercular agents (derivative of dihydropyridines) by employing the standard proportional method and a modified broth dilution-based assay. The results for isoniazid testing showed 100% concordance for sensitivity, specificity and reproducibility. In the case of microbial sensitivity test of lipophilic compounds, comparison of the results obtained from these two methods indicates a significant superiority of the modified method over the standard method. Considering the other advantages of this modified method, we concluded that this modified broth dilution-based assay could be utilized effectively for the susceptibility testing of new lipophilic compounds candidate as antitubercular agents.