Pathways to Next-Generation Antibiotics

Program Period: 
5/1/15 - 4/30/16

Cultivate a new class of antibiotic that can penetrate the cell walls of Gram-negative bacteria, leading to the establishment of an NIH center or industrial collaboration.

Drug-resistant bacteria is a growing and major problem worldwide. Recently, carbipenem-resistant Enterobacteriacea (CRE) killed a number of patients in hospitals. Few new antimicrobials have been discovered or developed by Biotech and Big Pharma over the past few decades, and resistance to virtually all antibiotics has occurred. Gram-negative pathogens are resistant to many antimicrobials that kill Gram-positive bacteria, primarily due to the relative impermeability of their outer membranes. BamA, an essential outer membrane protein present in all Gram-negative bacteria, acts as a receptor/conduit for entry of peptide toxins.  Its barrel structure appears to transition between open and closed conformations. This work focuses on a strategy to open the BamA channel using peptides, rendering the bacteria susceptible to antimicrobials that otherwise cannot cross the outer membrane barrier.

This work will set the stage for partnering with additional academic and industrial players and pursuing NIH, DARPA, or industrial funding, in line with President Obama’s recent requisition of $1.2B over the next five years for development of new antimicrobials.