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Systems Biology Insights into Antimicrobial Resistance Physiology
March 30, 2022 @ 12:00 pm - 1:00 pm UTC-5
Bactericidal antibiotics are conventionally understood to kill bacteria through a target-dependent process mediated by antibiotic inhibition of replicative machinery. However, several lines of evidence suggest that other aspects of bacterial physiology may also play a decisive, causal role. Yet, the interplay between bacterial metabolism and bactericidal antibiotic lethality is challenging to study due to the inherent complexity of bacterial metabolic networks and the confounding effects of bacterial metabolism on growth rate and the enzymatic turnover of antibiotic targets. Here we will present our recent efforts to tackle these challenges through the lens of interpretable machine learning and experimental evolution. We will demonstrate how network modeling can augment biochemical screens and be integrated with machine learning to directly reveal causal pathway mechanisms underlying cellular phenotypes. We will show how experimental evolution can lead to the discovery of novel antibiotic resistance alleles. From these collective approaches, we will discuss novel insights into the causal relationship between target- independent bacterial metabolism and both bactericidal antibiotic lethality and the evolution of antibiotic resistance. We will describe how antibiotic-induced nucleotide pool disruptions lead to elevated central carbon metabolism and bacterial respiration. We will show how transient antibiotic exposure selects for target-independent antibiotic resistance alleles and how such alleles are commonly found in clinical strains. We will discuss our new findings on how expression of antimicrobial resistance alleles alter bacterial metabolism and stress responses. We propose that such systems approaches can transform our understanding of antibiotic mechanisms and lead to rationally designed interventions for killing antibiotic resistant pathogens.
Jason Yang, Ph.D.
Assistant Professor and Chancellor Scholar,
Center for Emerging Pathogens,
Department of Microbiology, Biochemistry and Molecular Genetics,
Rutgers New Jersey Medical School
Discussion with students & Postdocs to follow.
Zoom Webinar: https://us02web.zoom.us/j/86289755333