Determination of minimum inhibitory concentration (MIC) of some 1,2,4-triazole derivatives with potential tuberculostatic and tuberculocidal ability in vitro


V. V. Zazharskyi, P. O. Davydenko, O. A . Bigdan, A. S. Hotsulia, O. M. Kulishenko, B. V. Gutyj, V. Z. Salata, M. S. Khimych, H. A. Skrypka, O. V. Naidich, M. V. Anforova, I. M. Popova, L. O. Franchuk-Kryva

The problem of tuberculosis infection caused by multidrug-resistant strains is becoming increasingly important in the world. This infectious disease poses a global health risk with an incidence rate of 8.8 million cases and a fatal outcome of 1.4 million. Coinfection with human immunodeficiency virus (HIV) increases the number of cases of tuberculosis and the development of active tuberculosis. Therefore, the search for substances with potential anti-TB activity is a promising way to solve this problem. 1,2,4-triazole derivatives – one of the interesting classes of anti-TB compounds. The study of their tuberculocidal, tuberculostatic properties, as well as MIC (minimum inhibitory concentration) was promising in relation to mycobacteria of different species. The work was conducted in 2019–2020 at Dnipro State Agrarian and Economic University. M. bovis and M. fortuitum mycobacterial species were selected for the study. The investigation of MIC levels for isoniazid, GKP-305, BKP-100 revealed that the growth of M. fortuitum had begun at 12th and 14th day on Sauton and Model media modified with 0.125% hydrogumate solution, respectively, whereas growth on pure Sauton and Model media was observed on the 25th and 28th day, respectively. It indicates that modification of Sauton and Model media with 0.125% hydrogumate solution doubles growth rate of M. fortuitum. As for isoniazid added to Sauton medium, MIC in case of M. fortuitum was impossible to determine since the growth was observed even at 50 µg/mL. With respect to GKP-305 added to Sauton medium, MIC was 50 µg/mL, which was concluded by the absence of growth. However, in the range of 25 to 0.19 µg/mL, isolated flakes of the colony with matte finish up to strong, noticeable strokes of the colonies with matte finish, which become well apparent at shaking, were observed. Having conducted studies on MIC determination on M. bovis and M. fortuitum using various growth media, it was established that MIC for isoniazid, GKP-305, BKP-100 applied on M. fortuitum in Sauton medium was 50 µg/mL; on Model medium, only MIC for BKP-100 on M. fortuitum could be determined, which was 50 µg/mL; similar results were obtained for 0.125% hydrogumate-modified Sauton medium and 0.125% hydrogumate-modified Model medium (MIC for BKP-100 was 50 µg/mL). The studies revealed the potential teberculocidal and tuberculostatic ability of the studied drugs GKP-305 and BKP-100 in relation to M. fortuitum and M. bovis. Isoniazid was used as a control. High efficacy was found in BKP-100 in relation to mycobacteria (MIC from 12.5 to 50 μg /mL). GKP-305 showed a tuberculostatic effect.

Keywords: Mycobacterium tuberculosis; M. bovis; M. fortuitum; GKP-305; BKP-100; isoniazid.

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