PL-1 Antibacterial drug discovery targeting bacterial RNA polymerase: myxopyronin (Myx)
Richard H. Ebright
Board of Governors Professor of Chemistry and Chemical Biology at Rutgers University and Laboratory Director at the Waksman Institute of Microbiology, NJ, USA
Myxopyronin (Myx) is a microbially produced antibiotic that inhibits bacterial RNA polymerase through a novel binding site and novel mechanism.
In basic research we have determined the binding site, mechanism, and structural basis of inhibition of bacterial RNA polymerase by Myx.
In translational research, we have performed structure-based design of novel Myx analogs, synthesized and evaluated >700 novel Myx analogs comprising four related chemical scaffold families, and we have identified compounds having improved in vitro and in vivo antibacterial activities, improved in vitro and in vivo pharmacological properties, and scalable syntheses.
Current top Myx analogs exhibit potent in vitro activity against Gram-positive bacteria and some Gram-negative bacteria--including drug-resistant, multi-drug-resistant, and extensively-drug-resistant strains--exhibit potent in vivo activity in mouse infection models, are orally available, and are non-toxic.