Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance

Abstract

While it is widely understood that antibiotic resistance is challenging the efficacy of our antibiotic therapies, there is a growing appreciation for the clinical importance of other ways that bacteria can survive antibiotic treatment. In particular, antibiotic tolerance describes a set of phenotypes where genetically susceptible bacteria can survive antibiotic treatment. Thus, there is a need for methods to improve our understanding of currently used antibiotics, as well as the discovery and development of new antibiotic therapeutic strategies, particularly focused on addressing antibiotic tolerance.

In this thesis, I present advancements to our understanding of antibiotic efficacy and our methods for discovering treatment strategies against antibiotic tolerant bacterial populations. First, I present an investigation into the metabolic processes that drive beta-lactam lethality, where we showed that drug-induced disruption of anabolic- catabolic homeostasis is an important factor for beta-lactam activity. Next, I describe an approach towards the discovery of antibiotic adjuvants for treating antibiotic tolerance. Finally, I present work towards the development of a method for discovering new antibiotics with activity against antibiotic tolerant bacteria. I describe characterization of compounds that were identified in primary screening efforts, as well as the results of a deep learning approach to this challenge in antibiotic discovery. Together, these projects demonstrate a set of advancements in our understanding of antibiotic activity and towards the challenge of antibiotic discovery.