Proteasome Accessory Factor-C (PafC) as a potential regulator of mycobacterial survival in multi drug-resistant tuberculosis patients

Abstract

Background: Mycobacterium tuberculosis (MTB) the causative agent of tuberculosis (TB) possesses the ability to survive inside its host courtesy various intrinsic factors involved. Proteasome machinery and drug efflux being the major role players apart from the presence of mycolic acid containing cell wall.

Objectives: To identify the role of proteasome accessory factor-C (PafC) in the survival of mycobacteria in the presence of fluoroquinolones (FQs).

Methods: The recombinant clones of mycobacteria containing sense and antisense copy of PafC were subjected to battery of tests. MICs of antimycobacterial drugs were tested in recombinant strains along with their growth and intracellular survival in J774A.1 cell lines. The bacteria were subjected to various stress conditions and the drug efficacy was tested. Samples from pulmonary TB (PTB) were collected to validate the work done in vitro.

Results and Conclusion: 4 major results were obtained through our molecular as well as clinical study:

• (i) PafC helps in the intracellular survival of the mycobacteria.

• (ii) PafC increases the drug efflux inside mycobacteria

• (iii) By slowing down the mycobacterial metabolism it probably aids it to survive the harmful effects of FQs.

PafC particularly overrides the effect of FQs in the mycobacteria most probably by activating the SOS DNA damage repair machinery. PafC is overexpressed in the case of multi drug resistant (MDR) patients but not so much in extensively drug resistant (XDR) patients. This highlights the specific role of PafC in the presence of FQs, which are the choice of drug for the treatment of MDR-TB.