IN VITRO ACTION OF THE DRUG CANDIDATE OF PBTZ169, HYDROCHLORIDE ACTION IN RESPECT OF CLINICAL STRAINS OF MYCOBACTERIUM TUBERCULOSIS WITH EXTENSIVE DRUG RESISTANCE

Goal of the study: to study the specific in vitro action of PBTZ169, hydrochloride, in respect of clinical strains of M. tuberculosis with extensive drug resistance (XDR).

Materials and methods. Strains of M. tuberculosis isolated from 20 XDR tuberculosis patients (10 strains from HIV positive patients and 10 strains from HIV negative patients) were used in the study, their susceptibility to 10 anti-tuberculosis first and second lines drugs plus linezolid was tested by Bactec MGIT 960. Bacteriostatic and bactericidal action of PBTZ169, hydrochloride, was defined as per the growth speed of M. tuberculosis strains in Bactec MGIT 960 compared to the growth of strains on the medium free from drugs and the medium containing control drugs (INH 0.1 мcg/ml, RIF 1 мcg/ml, AMK 1 мcg/ml and LFX 1.5 мcg/ml).

Results. The used clinical strains of Mycobacterium tuberculosis were resistant to 7-10 anti-tuberculosis drugs, of them 3 were resistant to linezolid. When testing bacteriostatic action it was found that PBTZ169, hydrochloride, in the concentration of 0.037 mcg/ml fully suppressed growth of all 10 strains isolated from HIV negative patients and of the majority of strains isolated from HIV positive tuberculosis patients (7 out of 10). In the same concentration PBTZ169HCl demonstrated bactericidal action in respect of all strains isolated from HIV negative tuberculosis patients and 4 out of 10 strains isolated from HIV positive tuberculosis patients. Forthe remaining 6 out of 10 strains from HIV positive tuberculosis patients minimum bactericide concentration made 0.111 mcg/ml.

1. WHO, Global Tuberculosis Report 2015. WHO/HTM/TB/2013.2 [Internet] URL: WHO, 2015. (In Russ.)

2. Annual Report 2015. TB Alliance. (In Russ.) http://www.tballiance.org/annualreport2015/xdr-tb.php

3. Epidemicheskaya situatsiya po tuberkulezu v Rossii. Protivotuberkuleznye meropriyatiya. [Tuberculosis epidemic situation in Russia. Tuberculosis control activities]. Federal Monitoring Center of Tuberculosis Transmission Control. (Available at: http://www.mednet.ru/images/stories/files/CMT/tb2015.pdf)

4. Makarov V., Manina G., Mikusova K. et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 2009, vol. 324(5928), pp. 801-804.

5. Matyugina E., Khandazhinskaya A., Chernousova L. et al. The synthesis and antituberculosis activity of 5’-nor carbocyclic uracil derivatives. Bioorg. Med. Chem., 2012, vol. 20, no. 22, pp. 6680-6686.

6. Neres J., Pojer F., Molteni E. et al. Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis. Sci. Transl. Med., 2012, vol. 4(150).

7. Pasca M.R., Degiacomi G., Ribeiro A. L. et al. Clinical isolates of Mycobacteriumtuberculosis in four European hospitals are uniformly susceptible to benzothiazinones. Antimicrob.Agents Chemother., 2010, vol. 54, no. 4, pp. 1616-1618.

8. Richter E., Rusch-Gerdes S., Hillemann D. First linezolid-resistant clinical isolates ofMycobacteriumtuberculosis. Antimicrob.Agents Chemother., 2007, vol. 51, no. 4, pp. 1534-1536.

9. Salman H. Siddiqi. Guidelines for Second-line Drug Susceptibility Testing in МGIT Based on Published Studies. Critical Concentrations and Procedures. H. Siddiqi. Salman. 2014, pp. 28.

10. Siddiqi S.H., Rusch-Gerdes S. MGIT Procedure Manual for BACTEC MGIT 960TB System. Guidelines on BACTEC MGIT 960 operation. 2006.

11. Trefzer C., Škovierová H., Buroni S. et al. Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2›-oxidase DprE1. J. Am. Chem., Soc., 2012, vol. 134, no. 2, pp. 912-915.