Aminopyridine- and aminopyrimidine-based serine/threonine protein kinase inhibitors are drug candidates for treating drug-resistant tuberculosis

Maslov DA1, Bekker OB1, Alekseeva MG1, Kniazeva LM1, Mavletova DA1, Afanasyev II2, Vasilevich NI2, Danilenko VN
About authors

1 Laboratory of Bacterial Genetics, Department of Genetics and Biotechnology,
Vavilov Institute of General Genetics of RAS, Moscow, Russia

2 Novie Nauchnie Tekhnologii Ltd., Moscow, Russia

Correspondence should be addressed: Valery N. Danilenko
ul. Gubkina, d. 3, Moscow, Russia, 119991; ur.ggiv@direlav

About paper

Funding: this work was supported by the Ministry of Education and Science of the Russian Federation (Grant No. 14.576.21.0019 dated July 27, 2014; ID RFMEFI57614X0019).

Contribution of the authors to this work: Maslov DA — experiment planning, data collection, analysis and interpretation, drafting a manuscript; Bekker OB — experiment planning, data analysis and interpretation, drafting a manuscript; Alekseeva MG, Kniazeva LM, Mavletova DA — data collection, participation in drafting of a manuscript; Afanasyev II, Vasilevich NI — provision of compound under study, participation in drafting a manuscript; Danileno VN — experiment planning, data interpretation, participation in drafting of a manuscript.

Received: 2017-01-30 Accepted: 2017-02-11 Published online: 2017-03-13

Tuberculosis (TB) is the world’s deadliest bacterial infection. Its causative agent Mycobacterium tuberculosis evolves into rapidly spreading multidrug-resistant and extensively drug-resistant (MDR and XDR) strains, which complicates the treatment. Therefore, the use of novel target-specific chemical compounds is crucial for the development of effective antituberculosis agents. Serine/threonine protein kinases (STPKs) of M. tuberculosis are currently considered as attractive drug targets. In turn, aminopyridines and aminopyrimidines that have not been used for TB treatment so far exhibit inhibitory activity towards STPKs. In this study we screened 192 aminopyridine- and aminopyrimidine-based compounds using the Mycobacterium smegmatis aphVIII+ test system designed to screen for active STPKs inhibitors. First, we selected 53 compounds with subinhibiting concentrations of up to 100 nmol/disk. Of them, 22 showed STPKs-inhibiting activity in the test system, which was confirmed in vitro on the M. tuberculosis PknA protein with a maximum of 26.9 ± 6.1 %. Toxicity testing was performed in vitro on human embryo fibroblasts using the MTT-assay. Ultimately, 3 relatively active and relatively non-toxic STPKs inhibitors were selected for further research as drug candidates for MDR-TB treatment.

Keywords: multidrug resistance, tuberculosis, Mycobacterium tuberculosis, Mycobacterium smegmatis, aphVIII, serine/threonine protein kinases, aminopyridines, aminopyrimidines, inhibitors