This research addresses the hierarchical usage of carbon sources by enteric bacteria, and the kinetic of growth transition that occurs when bacteria switch from one to another carbon source. This phenomenon, known as diauxic growth, was discovered by Jacques Monod 65 years ago. It was commonly thought to result from catabolite repression, a regulatory response well characterized molecularly in E. coli and wide spread among microbes. However, recent studies establish that catabolite repression is about coordinating carbon metabolism with other sectors of metabolism and cell growth, and not about prioritizing the use of carbons.
This research aims to elucidate the regulatory strategies enteric bacteria employ to choose among an infinite combination of carbon sources in the environment (often taking the fast-metabolizing carbons first), and the kinetic mechanism that enable them to switch carbon source rapidly when the preferred one runs out. The research will be carried out using a combination of approaches: traditional biochemical and molecular biology approaches to quantify the pools of key signaling molecules; quantitative proteomics to characterize protein synthesis and turnover that result in proteome-wide remodeling during growth transitions; synthetic genetic constructs that allow one to quantitatively probe the effect of changing metabolic fluxes and protein loads on growth transitions; microfluidic-based approaches to characterize cell growth, gene expression, and signaling molecules at a cell-by-cell level; and quantitative phenomenological approaches to develop coarse- grained kinetic models that capture the physiological responses and relate them to the underlying regulatory mechanisms. The proposed work is in essence a major extension of the highly successful approach our lab has developed in recent years to relate gene expression to growth physiology, but from the steady state to the kinetic domains. The output of this research, a quantitative predictive model of diauxic growth relating key molecular interactions to physiological behaviors, will provide a prototype for modeling the kinetics of growth transitions relevant to a wide variety of other problems ranging from the response of bacteria to antibiotic, to the kinetics of differentiation an development after entering the stationary phase. The specific knowledge on how enteric bacteria select their carbon preferences may be exploited in metabolic engineering applications to remove or alter the order of carbon consumption, while knowledge on the regulatory strategies of growth transitions may lead to new classes of antimicrobial strategies aimed at slowing down growth recovery.

Public Health Relevance

The rapid adaptive response of enteric bacteria to different nutrient and stress conditions is critical to the selective fitness of these bacteria in the human gut and outside. Quantitative characterization and analysis of the adaptive responses will be used to derive a predictive theory of growth transition kinetics and may guide the formulation of novel antimicrobial approaches aimed at slowing down the speed of growth recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM109069-03S1
Application #
9275880
Study Section
Program Officer
Reddy, Michael K
Project Start
2014-02-17
Project End
2018-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Cremer, Jonas; Arnoldini, Markus; Hwa, Terence (2017) Effect of water flow and chemical environment on microbiota growth and composition in the human colon. Proc Natl Acad Sci U S A 114:6438-6443
Dai, Xiongfeng; Zhu, Manlu; Warren, Mya et al. (2016) Reduction of translating ribosomes enables Escherichia coli to maintain elongation rates during slow growth. Nat Microbiol 2:16231
Cremer, Jonas; Segota, Igor; Yang, Chih-Yu et al. (2016) Effect of flow and peristaltic mixing on bacterial growth in a gut-like channel. Proc Natl Acad Sci U S A 113:11414-11419
Basan, Markus; Zhu, Manlu; Dai, Xiongfeng et al. (2015) Inflating bacterial cells by increased protein synthesis. Mol Syst Biol 11:836
Hermsen, Rutger; Okano, Hiroyuki; You, Conghui et al. (2015) A growth-rate composition formula for the growth of E.coli on co-utilized carbon substrates. Mol Syst Biol 11:801

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