Secreted proteins of Mycobacterium tuberculosis as therapeutic targets for drug discovery.

Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis secretes proteins during the host-pathogen interaction that facilitate its survival and/or virulence within host cells. Key examples include EsxA and EsxB, CpnT/TNT, phosphatases (SapM, PtpA, PtpB), protein kinase G (PknG), the antigen 85 (ag85) complex, acyl Carrier Protein (AcpM), lipoproteins, and heat shock proteins (Hsps). Together, these secreted factors disrupt host immune responses such as phagosome maturation, antigen presentation, cytokine production, and autophagy thereby aiding in survival of these obligate intracellular bacteria. Several secreted proteins are emerging as therapeutic targets to help meet the need for shorter, more effective, and better tolerated treatment regimens for tuberculosis. Here, we review the current understanding of the major secreted proteins of M. tuberculosis. We also discuss progress in the discovery and development of drugs targeting these proteins. Overall, targeting M.tuberculosis secreted proteins remains largely in the preclinical stages of drug development. Current limitations include low potency, off-target activity, and redundancy among secreted proteins.