Principal Investigator:
Jason Sello, PhD, Assistant Professor
Department of Chemistry
Brown University
Providence, RI
Brief Description:
Infectious diseases are the second leading cause of death – globally. Antibiotic drug resistance is a major clinical and societal problem, with many long-standing antibiotics no longer affective against several emergent pathogenic microbial strains. The capability of bacteria to routinely develop resistance to virtually any antibacterial agent necessitates a continuous and urgent search for new, effective drugs.
A new group of chemical entities that have attracted attention as potential antibacterial drugs are the enopeptins. Like many of the most important antibacterial drugs, these acyldepsipeptides are derived from a strain of soil-dwelling bacteria. They have significant and compelling advantages over other antibacterial agents. They exhibit potent activity against Gram-postitive, multi-drug resistant pathogens (MRSA and VRE), is non-toxic to eukaryotes, and binds a clinically distinct novel protein target to have an unprecedented mechanism-of-action. Their apparent lack of cross-resistance for all antibacterial agents, on the market or in clinical development, has been ascribed to their unique mechanism-of-action and binding site of the casein lytic protease (ClpP). Although the enopeptins derived from the soil bacteria are unstable and exhibit poor efficacy in mouse models of infection, a medicinal chemistry program focused on the core structure of the enopeptins resulted in a derivative that has marked improvement in antibacterial activity and in in vivo efficacy in mouse models of infections. It is anticipated that further improvements to the structures of the enopeptins will yield better drug leads. Further, it is hypothesized that enopeptin derivatives could be used to compromise virulence of pathogens via their binding to ClpP, an essential protein for virulence in pathogenic bacteria.
The invention is a novel method for the chemical synthesis of enopeptin derivatives that will yield compounds that can affect the viability of bacteria or the ability of bacteria to cause disease. The new drugs can be potentially administered by any route such as oral, topical, intravenous, etc., and this technology has implications for inhibiting growth and/or rapidly killing dividing cells in the treatment of inflammatory and autoimmune diseases, cancer, or diabetic retinopathy, among many others.
The application is for use as an antibiotic therapeutic to eradicate microbial infections in humans and animals.
Information:
US patent 9,193,767 is issued (11/24/2015).
European patent 2691396 is granted.
US patent application 14/924,667 is pending.