Resistance-Guided Antibiotic Discovery

The crisis of antibiotic resistance demands new strategies to discover the next generation of antimicrobial agents. This will require innovation in the strategies we use to find new drug-like molecules and their deployment in treating disease causing infectious organisms. To address the antibiotic crisis, we propose to use resistance itself as a target for drugs and also to use resistance as a means to sift through candidate compounds for new antibiotics. Our efforts in these areas are focused on a re-exploration of the sources of first generation antibiotics, the environmental microbes (bacteria and fungi) that have proven such a rich source of drugs. In the first case of targeting resistance directly, we are identifying molecules produced by environmental microbes that directly and indirectly block resistance. Such molecules, called antibiotic adjuvants, are deployed in combination with first generation antibiotics to overcome resistance and rescue the activity of our legacy drugs. In the second case, we are using resistance to identify potential antibiotic producing soil microbes. Here our logic is based on the understanding that these soil microbes must have intrinsic resistance to a given antibiotic class in order to avoid committing suicide during antibiotic production. This strategy has enabled us to identify new members of antibiotic classes that have the potential to expand the antibiotic arsenal. Both of these approaches use resistance in different ways to address the antibiotic crisis, but have in common harnessing the very essence of the problem to deliver solutions for next generation drugs.