The goal of this project is to use innovative systems biology and synthetic biology approaches to quantitatively characterize and analyze bacterial gene regulatory networks underlying cellular responses to antibiotics, the formation of persisters and the emergence of resistance. With the alarming spread of antibiotic-resistant strains of bacteria, a better understanding of the specific sequences of events leading to cell death from bactericidal antibiotics is needed for future antibacterial drug development. Accordingly, there is a need for systems biology and synthetic biology approaches to discern the interplay between genes, proteins and pathways in furthering our understanding of how bacteria respond and defend themselves against antibiotics. The implications of the underlying logic of genetic networks are difficult to deduce through experimental techniques alone, and successful approaches will in many cases, involve the union of new experiments and computational modeling techniques. To address this problem, we have developed computational-experimental methods that enable construction of quantitative models of gene, protein and metabolite regulatory networks using expression measurements and no prior information on the network structure or function. In this project, we will use these approaches to reverse engineer bacterial gene regulatory networks underlying cellular responses to antibiotics, the formation of persisters and the emergence of resistance. The resulting networks and pathways will be analyzed to gain insight into the regulatory control of the associated biological processes, and the network models will be used to identify key regulators and mediators for a variety of phenotypic responses. This work could lead to new insights into the stress response of bacteria and the identification of novel targets for drug discovery, e.g., ones that overcome bacterial protective mechanisms or activate bacterial programmed cell death. This project may thus enable the development of novel classes of antibiotics that account for and utilize the complex regulatory properties of genetic networks.
| Cohen, Nadia R; Ross, Christian A; Jain, Saloni et al. (2016) A role for the bacterial GATC methylome in antibiotic stress survival. Nat Genet 48:581-6 |
| Lobritz, Michael A; Belenky, Peter; Porter, Caroline B M et al. (2015) Antibiotic efficacy is linked to bacterial cellular respiration. Proc Natl Acad Sci U S A 112:8173-80 |
| Belenky, Peter; Ye, Jonathan D; Porter, Caroline B M et al. (2015) Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage. Cell Rep 13:968-80 |
| Cameron, D Ewen; Collins, James J (2014) Tunable protein degradation in bacteria. Nat Biotechnol 32:1276-81 |
| Pandey, Shree P; Winkler, Jonathan A; Li, Hu et al. (2014) Central role for RNase YbeY in Hfq-dependent and Hfq-independent small-RNA regulation in bacteria. BMC Genomics 15:121 |
| Dwyer, Daniel J; Belenky, Peter A; Yang, Jason H et al. (2014) Antibiotics induce redox-related physiological alterations as part of their lethality. Proc Natl Acad Sci U S A 111:E2100-9 |
| Brynildsen, Mark P; Winkler, Jonathan A; Spina, Catherine S et al. (2013) Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production. Nat Biotechnol 31:160-5 |
| Modi, Sheetal R; Lee, Henry H; Spina, Catherine S et al. (2013) Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499:219-22 |
| Belenky, Peter; Camacho, Diogo; Collins, James J (2013) Fungicidal drugs induce a common oxidative-damage cellular death pathway. Cell Rep 3:350-8 |
| Cohen, Nadia R; Lobritz, Michael A; Collins, James J (2013) Microbial persistence and the road to drug resistance. Cell Host Microbe 13:632-42 |
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