Targeting ESX-1 Secretion System to Control Mycobacterial Infection

Abstract

Resistance to anti-tuberculosis (TB) drug is a major public health problem threatening the progress that has been made in TB care and control worldwide. The rise of mycobacterium resistance to traditional antibiotics has motivated recent efforts to discover new drug candidates that target virulence factors. In this work, we have developed a robust high-throughput screen (HTS) assay that directly measures the activity of ESX-1 secretion. This screen identifies small molecules that inhibit ESX-1 secretion and thereby bacterial virulence without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1 dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacterial. Importantly, our data illuminate the great advantage of the ESX-1 inhibitors in the low risk of mycobacterium developing resistance in vitro as compared with traditional anti-TB drug as well as in the strong potency against latent mycobacterial infection. Thus targeting ESX-1 may lead to the development of therapeutics to drug resistant-tuberculosis.

Keywords: ESX-1 Secretion System, IMB-BZ, inhibition, mycobacterial infection