UNCOVERING SYNERGISTIC ANTIBIOTIC COCKTAILS WITH COMPARATIVE GENOMICS

PROJECT SUMMARYThe continued rise of antibiotic resistance is a major threat to public health and has already resulted in anumber of pathogens resistant to all available antibiotics. About 80% of antibiotics are derived frommicroorganisms that have used them against their competitors for millions of years. Yet, antibioticresistance has remained at remarkably low levels in nature, in stark contrast to the dramatic increase inresistance among human pathogens. A critical gap in our knowledge is how naturally antibiotic-producing microorganisms have mitigated the rise of resistance in their competitors. Here wehypothesize that antibiotic producers have not only evolved antibiotics but also a strategy for wieldingthem sustainably. We propose that this strategy involves the use of antibiotic cocktails that actcollectively to ward off resistance, increase potency, and target a greater breadth of organisms.Comparative genomics provides a means for uncovering this strategy by leveraging the abundance ofrecently-sequenced microbial genomes. In this project, we will develop and experimentally validate anovel bioinformatics technique to discover new candidate antibiotics and combinations of antibioticswith synergistic activities. The goals of this project are to both supplement our existing arsenal ofantibiotics and shed light on sustainable ways for employing antibiotics in the clinic. This project is highlyinnovative because it will develop a completely new method for mining microbial genomes for naturalproducts such as antibiotics, and it will demonstrate the advantages of considering antibiotics in aholistic context rather than in isolation. Furthermore, it may challenge the current clinical paradigm ofantibiotic monotherapy by determining whether cocktails of antibiotics offer a strategic advantage. Thisproject holds the promise of changing clinical practice by extending the useable lifetime of antibiotics,revealing new drug candidates for future research, and developing a novel technical capability withmedical applications. These outcomes are crucial for public health at a time when the rise of antibioticresistance shows no signs of abating and its costs continue to mount.