题目：Development of new antibiotics to treat tuberculosis
Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed towards new targets are highly coveted.
MmpLs (Mycobacterial membrane proteins Large) which play crucial roles in transporting lipids, polymers and immunomodulators, and that also extrude therapeutic drugs, are amongst the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of Mycobacterial MmpL3 alone and in complex with four TB drug candidates including SQ109 (in Phase 2b-3 clinical trials) are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235 and ICA38 bind inside the transmembrane region and disrupt these Asp-Tyr pairs. Strikingly, rimonabant, the first CB1 antagonist, was also found to target the same binding pocket. It is remarkable that rimonabant adopts completely different binding modes to inhibit mycobacterial MmpL3 and human CB1 receptor. Since MmpL3 and its orthologues are well conserved across mycobacteria and corynebacteria, these results may facilitate the development of new drugs which are broadly effective against these and other human pathogenic infectious diseases including TB, leprosy and diphtheria. In addition, this is the first report describing structures of drug candidates which can block the proton motive force to inhibit an RND family member, many of which are important targets for anti-bacterial drug discovery. These data will therefore provide inspiration for the design of new classes of antibiotics.