Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents

The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhib-itors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithro-mycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a sin-gle agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the poten-tial for use in new regimens against drug-susceptible and drug-resistant TB.

Automated summary

A series of macrolides called sequanamycins have been discovered, showing outstanding activity against drug-resistant tuberculosis. The lead compound SEQ-9 exhibited efficacy as a single agent and in combination with other TB drugs in mouse models. These findings support further investigation of sequanamycins as potential clinical candidates against drug-resistant TB.