Specific targeting to the Mycobacterium tuberculosis P-type ATPase Membrane Transporter, CtpF, of antituberculous compounds obtained by structure-based design.

Abstract

The resurgence of Mycobacterium tuberculosis (Mtb) strains that resist anti-tuberculosis (anti-TB) drugs used currently stresses the search for more effective low-toxicity drugs against new targets. Due to their role in ion homeostasis and virulence, Mtb plasma membrane P-type ATPases are interesting anti-TB targets, in particular, the Ca2+ transporting P2-type ATPase CtpF which is involved in oxidative stress response and persistence. In this study, the effect on the transcription level of the ctpF gene and other Mtb P2-type ATPases of two anti-Mtb hits was assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Both anti-Mtb hits ZINC14541509 and ZINC63908257 had been previously identified using pharmacophore-based virtual screening and MM-GBSA binding free energy. In addition, the bacterial activity of both compounds on Mycobacterium bovis was evaluated to see whether or not there is an effect on other mycobacteria of the Mtb complex. qRT-PCR experiments showed that the ctpF transcription level was significantly higher in the presence of both compounds, especially ZINC14541509, strongly suggesting that CtpF may be a specific target of the selected compound. ZINC14541509 should be considered as an alternative for the structural-based design of novel anti-TB drugs.