Myxopyronins

About

Summary: Bacterial infectious diseases kill 100,000 persons each year in the US and 11 million persons each year worldwide, representing nearly a fifth of deaths each year worldwide.  For six decades, antibiotics have been our bulwark against bacterial infectious diseases.  However, now this bulwark is collapsing.  For all major bacterial pathogens, strains resistant to at least one current antibiotic have arisen, and, for several bacterial pathogens, strains resistant to all current antibiotics have arisen.  There is an urgent national and international need for new classes of antibacterial agents effective against bacterial pathogens resistant to current antibacterial agents. Myxopyronin (Myx) is a microbially produced antibiotic that functions by inhibiting bacterial RNA polymerase through a novel binding site and novel mechanism.  Rutgers researchers defined the binding site, mechanism, and structural basis of inhibition by Myx.  Rutgers researchers then performed structure-based design of novel Myx analogs, synthesized and evaluated >600 novel proprietary Myx analogs comprising three related chemical scaffold families (PYs, APYs, and APPs), and 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 and multi-drug-resistant strains--and exhibit potent in vivo activity in a mouse methicillin-resistant Staphylococcus aureus (MRSA) infection model with either intravenous dosing or oral dosing. In the presence of an outer-membrane-disruptor serving as "potentiator," current top Myx analogs exhibit potent in vitro activity against additional Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli--including colistin-resistant mcr-1 strains of E. coli--and exhibit potent in vivo activity in a mouse P. aeruginosa infection model with intravenous dosing.   Market Application: •  Treatment of bacterial infections (particularly drug-resistant and multi-drug-resistant bacterial infections)   Advantages: •  First-in-class compounds (PYs/APYs, APPs) •  Novel target and mechanism •  Broad-spectrum antibacterial activity (most Gram-positive bacteria and some Gram-negative bacteria •  Additional Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae in combination with outer-membrane disruptor as potentiator) •  Active against drug-resistant strains (active against strains resistant to rifamycins, beta lactams, tetracyclines, macrolides, fluoroquinolines, aminoglycosides, lincosamides, oxazolidinones, lipopeptides, glycopeptides, mupirocins) •  Active against both replicating and non-replicating bacteria •  Active against biofilms •  Bactericidal •  Additive effects when co-administered with rifamycins •  Suppressed resistance emergence when co-administered with rifamycins •  Orally available