Conjugated Oligoelectrolyte Antibiotics: Mechanism of Action

The new objectives of this project are to:

• Determine the mechanism of Conjugated Oligoelectrolyte (COE) action and resistance.  The effort will include evolution and sequencing of drug-resistant mutants, followed by comparative mutational analysis. These studies will be supplemented by examination of bacterial membrane properties through permeability assays.
• Interrogate specific structural modules within the COE molecular scaffold to identify and optimize key components that correlate with desired efficacy and toxicity profiles.
• Optimize COE molecular structures for pathogens of military interest.  This effort will tightly integrate efforts at the Wound Infections Department (WID) at WRAIR and ICB through a newly established collaboration. Special emphasis will be placed on the potential antibiotic activity of COEs toward Acinetobacter baumannii and Pseudomonas aeruginosa, nosocomial pathogens responsible for 40% of all mono-microbial infections in Wounded Warriors.

It is worth highlighting that COEs have no structural relationship to any known antibiotic. These studies may therefore yield the first fundamentally new class of broad-spectrum antibiotics in fifty years. COE synthesis is relatively cheap and easy to scale up compared to conventional antibiotics, with minimal decomposition even after years in solid or solution form without refrigeration. Up to now, all of the advances have been through intuition.  This ICB study program is the first mechanism-based and Army-integrated effort in this area of basic science.