Therapeutics for Drug-Resistant Bacterial Infections - Myxopyronins

Invention Summary:

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 inhibits 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.

Our current lead molecule APY 281 exhibits 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," APY 281 exhibits 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.

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
• Active against drug-resistant strains (active against strains resistant to rifamycins, lipiarmycins, beta lactams, tetracyclines, macrolides, fluoroquinolines, aminoglycosides, lincosamides, oxazolidinones, lipopeptides, glycopeptides, mupirocins)
• Active against priority public-health pathogens (Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus pneumoniae, Clostridium difficile, and Mycobacterium tuberculosis without potentiator; Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli in combination with potentiator)
• Active against priority biodefense pathogens (Bacillus anthracis, Francisella tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia pseudomallei, Brucella melitensis)
• 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

Primary Indications:

• Treatment of gram- positive bacterial infections (particularly drug-resistant and multi-drug-resistant bacterial infections MRSA, VRSA, VRE, MDR-TB) (1) iv with oral step down and, (2) iv in combination with a potentiator, gram negative bacterial infections - Pseudomonas, Acinetobacter, and Enterobacteriaceae

Intellectual Property & Development Status:

• Large patent portfolio containing both issued and pending patents on compositions of matter and uses
• Advanced lead compounds with IND enabling data and with in vivo proof of concept in Gram-positive and Gram-negative animal infection models- some Toxicology completed