The prevalence of multi-drug resistant bacterial pathogens has increased dramatically in recent decades, threatening our ability to treat infections. Though pathogens may develop antibiotic resistance through individual mutations, the most common means of acquiring resistance is through horizontal gene transfer (HGT), enabling pathogens to rapidly develop insensitivity to antibiotic therapy. Therefore, it is essentil to systematically characterize the many genetic reservoirs of antibiotic resistance genes (or 'resistomes') accessible to pathogens. The human gut microbiota harbor a particularly important resistome to study due to (1) easy contact and genetic exchange between commensals and pathogens, (2) historic under sampling of this community with culture-based approaches, and (3) the dynamic properties of community composition in early human life. We propose to deeply characterize the development of the intestinal resistome in the first two years of life using a powerful, culture- independent combination of functional metagenomics selections with next-generation sequencing. We seek to achieve two overarching goals. First, we will define how genetic and environmental factors (including antibiotic treatment) affect the assembly and dynamics of the infant gut resistome. Second, we will understand how the potential for mobilization of the resistome (defined by association of resistance genes with mobile genetic elements) influence the stability of this critical ecosystem. To this end, our first specific aim i to characterize resistome development in healthy infants through testing the hypothesis that antibiotic exposure, postnatal age, and shared environment and host genetics drive the abundance, diversity and dissemination of gut resistomes.
Our second aim i s to understand pathologic resistome development of very-low birth weight (VLBW) infants by testing the hypothesis that spectrum and duration of antibiotic therapy drive the abundance, diversity, and dissemination of the gut resistome in these characteristically low-diversity microbiotas. In both aims, we will focus on diversity, abundance, and genetic context of resistance genes in the developing microbial community. We will enhance fundamental understanding of host-associated microbial community dynamics in three significant ways: (1) Illuminating assembly and dynamics of the resistome in developing gut microbiota of infants sampled longitudinally over the first two years of life, (2) defining the role of genetic exchange in developing microbial communities using antibiotic resistance and associated mobile genetic elements as clinically-relevant and easily-assayed microbial community functions, and (3) applying technological innovations in metagenomics, next-generation sequencing, and computational biology to dramatically increase throughput and decrease costs of studying microbial community functions. Potential impacts of our study are: (1) developing a novel framework for economical, high-throughput characterization of microbial community functions, (2) providing a basis for future work to mitigate infant morbidity and mortality in the neonatal period resulting from inappropriate colonization dynamics of gut microbiota, and (3) establishing a translational evidence base for more prudent use of antibiotics.

Public Health Relevance

Antibiotic resistance in human pathogens has increased dramatically over the past decades, challenging our ability to treat bacterial infections. Our project applies innovative, high-throughput, and economical methods for understanding how resistance develops in the normal bacterial inhabitants of the human body (the human microbiota) during the first few years of life, and understanding how this resistance may transfer to other bacteria, including pathogens. Our results should aid development of new methods to curb the spread of resistance, and inform more prudent and predictive use of antibiotics in the clinic, in our community, and worldwide.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM099538-01A1
Application #
8412917
Study Section
Special Emphasis Panel (ZGM1-GDB-2 (MC))
Program Officer
Sledjeski, Darren D
Project Start
2012-12-28
Project End
2016-11-30
Budget Start
2012-12-28
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$304,000
Indirect Cost
$104,000
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Gibson, Molly K; Wang, Bin; Ahmadi, Sara et al. (2016) Developmental dynamics of the preterm infant gut microbiota and antibiotic resistome. Nat Microbiol 1:16024
Pehrsson, Erica C; Tsukayama, Pablo; Patel, Sanket et al. (2016) Interconnected microbiomes and resistomes in low-income human habitats. Nature 533:212-6
Langdon, Amy; Crook, Nathan; Dantas, Gautam (2016) The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med 8:39
Potter, Robert F; D'Souza, Alaric W; Dantas, Gautam (2016) The rapid spread of carbapenem-resistant Enterobacteriaceae. Drug Resist Updat 29:30-46
Gasparrini, Andrew J; Crofts, Terence S; Gibson, Molly K et al. (2016) Antibiotic perturbation of the preterm infant gut microbiome and resistome. Gut Microbes 7:443-9
Kaminski, James; Gibson, Molly K; Franzosa, Eric A et al. (2015) High-Specificity Targeted Functional Profiling in Microbial Communities with ShortBRED. PLoS Comput Biol 11:e1004557
Pesesky, Mitchell W; Hussain, Tahir; Wallace, Meghan et al. (2015) KPC and NDM-1 genes in related Enterobacteriaceae strains and plasmids from Pakistan and the United States. Emerg Infect Dis 21:1034-7
Forsberg, Kevin J; Patel, Sanket; Wencewicz, Timothy A et al. (2015) The Tetracycline Destructases: A Novel Family of Tetracycline-Inactivating Enzymes. Chem Biol 22:888-97
Clemente, Jose C; Pehrsson, Erica C; Blaser, Martin J et al. (2015) The microbiome of uncontacted Amerindians. Sci Adv 1:
Gibson, Molly K; Crofts, Terence S; Dantas, Gautam (2015) Antibiotics and the developing infant gut microbiota and resistome. Curr Opin Microbiol 27:51-6

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