Antibiotic agents target only a small number of cellular targets in bacteria – translation, transcription, cell wall biosynthesis, and DNA replication. Each of these targets is a major consumer of the total energetic output of the cell. While these targets have been well defined, the metabolic perturbations produced by their inhibition are poorly understood. We are applying genome-scale fluxomics, metabolite profiling, and metabolic modeling to define the pathogen metabolic response to antibiotic therapy.
We find that the metabolic stress responses are major arbiters of antibiotic efficacy and define many of the key phenotypes that have been long known but poorly understood, such as persistence and bacteriostasis. We have used this data to show that bactericidal antibiotics, which kill bacteria, uniformly induce metabolic acceleration and dysregulation that lead to toxic end product formation (such as modifications to the proteome and to the nucleotide pool) which can promote mutagenesis and drug resistance. We are further designing synthetic systems to artificially perturb basal cellular metabolism, with the goal to identify drug targets that can potentiate antimicrobial activity.