A Novel Antibiotic Strategy Exploiting Metabolite Self-Toxicity

Type of Award: Catalyst
Date Awarded: March 2017
Award End Date: February 2019
Amount Awarded: $ 250,000.00
PI(s): Keith Tyo, NU; Scott Franzblau, UIC;

Abstract: Strains of multidrug resistant Mycobacterium tuberculosis (M. tb) are appearing faster than new antibiotics, threatening a wide-spread re-emergence. This trend is true for many infectious bacteria, and the NIH has made combating antibiotic resistance a key priority. The standard drugging approach of directly inhibiting essential pathways may be exhausted. We propose a fundamentally different approach that could target a new set of non-essential M. tb proteins (Fig. 1). Native metabolites that act as competitive inhibitors (CIs) at high levels, can be artificially raised by drug combinations. This proposal seeks to identify potentially toxic native CIs and devise strategies to increase their concentration by modulating enzymatic producers/consumers of the CI (PCI/CCI). If successful, a whole range of compounds that target non-essential enzymes (PCI/CCI) could be made antimicrobial by potentiating this self-toxicity.