Abstract: Antibiotic resistance is a mounting problem at the global scale that compromises the use of these drugs as our main defense against microbial infections. The antibiotics themselves act as a selective pressure for resistance, and the present solution of developing new antibiotic classes only delays the problem until new resistance emerges. My goal is to develop entirely new strategies to fight pathogenic bacteria by targeting the social interactions involved in pathogenesis. The goal is motivated by the realization that most pathogenic bacteria are not isolated organisms, but rather live in multicellular communities called biofilms where cell-cell interactions are essential. Our recent applications of social evolutionary theory to microbiology have already shown that biofilm formation, quorum sensing and virulent secretions are highly dependent on interactions among cells and that the fate of cooperative interactions is challenged by the presence of competing strains. Therefore, I hypothesize that therapies that target social interactions can reduce the virulence of bacterial populations without creating strong selection for resistance. I will test this hypothesis in the bacterium Pseudomonas aeruginosa, an opportunistic human pathogen notorious for infecting the lungs of cystic fibrosis patients by forming antibiotic resistant biofilms. The formation of robust biofilms requires well-regulated secretion of rhamnolipid biosurfactants, which are self-produced dispersants that play a major role in shaping biofilm 3-D structure. I will investigate the conditions that lead to unregulated rhamnolipid secretion as potential strategies for self-induced biofilm dispersal. For the period of this award I will carry out three complementary research avenues that will combine quantitative-experimental and computational methods: (1) I will characterize the dynamic response of the quorum sensing regulation of biosurfactant secretion in P. aeruginosa. I will carry this out by selectively deleting genes in the regulatory pathway and measuring system response using reporter fusions. (2) I will develop the next generation of realistic 3-D computational biofilm models. I will apply these models to rationally design strategies that induce self-promoted biofilm dispersal. (3) I will quantify the networks of social interactions and test experimentally strategies that disperse biofilms by perturbing those interactions. These studies expand the applications of quantitative social evolution to molecular and cell biology, and will provide for the first time a systems view of microbial groups that integrates the dynamic observations of genetic and phenotypic diversity among cells with the importance of cellular cooperation. The project leverages my unique expertise at the interface of engineering, systems biology and evolution, and applies this expertise towards new therapies against microbial infection. Public Health Relevance: Antibiotics are our main line of defense against bacterial infections, but they face the global threat of emerging resistance. I propose to develop entirely new treatment strategies by unveiling the molecular mechanisms and evolutionary principles governing interactions in biofilms of pathogenic bacteria. This research will prove of value in the rational design of new clinical interventions that specifically target cellcell interactions.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2OD008440-01
Application #
8145983
Study Section
Special Emphasis Panel (ZGM1-NDIA-S (01))
Program Officer
Basavappa, Ravi
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2011-09-30
Budget End
2016-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$2,739,000
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Xavier, Joao B (2016) Sociomicrobiology and Pathogenic Bacteria. Microbiol Spectr 4:
Wexler, Aaron G; Bao, Yiqiao; Whitney, John C et al. (2016) Human symbionts inject and neutralize antibacterial toxins to persist in the gut. Proc Natl Acad Sci U S A 113:3639-44
Buffie, Charlie G; Bucci, Vanni; Stein, Richard R et al. (2015) Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517:205-8
Madsen, Jonas S; Lin, Yu-Cheng; Squyres, Georgia R et al. (2015) Facultative control of matrix production optimizes competitive fitness in Pseudomonas aeruginosa PA14 biofilm models. Appl Environ Microbiol 81:8414-26
Deforet, Maxime; van Ditmarsch, Dave; Xavier, João B (2015) Cell-Size Homeostasis and the Incremental Rule in a Bacterial Pathogen. Biophys J 109:521-8
Boyle, Kerry E; Monaco, Hilary; van Ditmarsch, Dave et al. (2015) Integration of Metabolic and Quorum Sensing Signals Governing the Decision to Cooperate in a Bacterial Social Trait. PLoS Comput Biol 11:e1004279
Bucci, Vanni; Xavier, Joao B (2014) Towards predictive models of the human gut microbiome. J Mol Biol 426:3907-16
Deng, Pan; de Vargas Roditi, Laura; van Ditmarsch, Dave et al. (2014) The ecological basis of morphogenesis: branching patterns in swarming colonies of bacteria. New J Phys 16:015006-15006
Korolev, Kirill S; Xavier, Joao B; Gore, Jeff (2014) Turning ecology and evolution against cancer. Nat Rev Cancer 14:371-80
Deforet, Maxime; van Ditmarsch, Dave; Carmona-Fontaine, Carlos et al. (2014) Hyperswarming adaptations in a bacterium improve collective motility without enhancing single cell motility. Soft Matter 10:2405-13

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