The interaction topology of Mycobacterium tuberculosis genes response to capreomycin and novel clues for more drug targets.

The resurgence of tuberculosis (TB) and emergence of multidrug-resistant TB (MDR-TB) are significant obstacles to stop TB treatment. Capreomycin (CPM) is regarded as an ideal second-line treatment for TB as well as for MDR-TB. However, the inexorable emergence of capreomycin resistant TB cases accentuates the urgent need for more detailed characterization of CPM targets. Most of these are single gene mutation, such as those involved in the complex formation of ribosomal 30S initiation, inhibit protein synthesis, affect 50S ribosomal protein L10, control transcription and translation of operon rpIJL-rpoBC. A new paradigm integrating gene, small metabolites, protein and underlying signaling pathway to shed light on the physiology, pathogenesis, and network of pathogen response is emerging. This model holds great promise to unravel the intricacy of drug action. However, to our knowledge, no such work regarding Mycobacterium tuberculosis response to capreomycin exposure was ever reported. We employed the data mining to construct an interaction topology of M. tuberculosis genes response to capreomycin. Most valuable genes were summarized for further experimental validation based on this topology. Dampening the virulence factors and respiratory of M. tuberculosis might be the new targets of CPM beyond Rv1364c, pe_pgrs38, pe_pgrs51 which are the salient nodes of the network and represent most promising new capreomycin targets meriting further exploration. This work will facilitate further investigation of capreomycin targets against M. tuberculosis and be conducive to novel TB drug discovery.