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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-GDB-2 (MC))
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Sledjeski, Darren D
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Washington University
Schools of Medicine
Saint Louis
United States
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Potter, Robert F; Lainhart, William; Twentyman, Joy et al. (2018) Population Structure, Antibiotic Resistance, and Uropathogenicity of Klebsiella variicola. MBio 9:
Ferreiro, Aura; Crook, Nathan; Gasparrini, Andrew J et al. (2018) Multiscale Evolutionary Dynamics of Host-Associated Microbiomes. Cell 172:1216-1227
Tsukayama, Pablo; Boolchandani, Manish; Patel, Sanket et al. (2018) Characterization of Wild and Captive Baboon Gut Microbiota and Their Antibiotic Resistomes. mSystems 3:
Goldner, Nicholas K; Bulow, Christopher; Cho, Kevin et al. (2018) Mechanism of High-Level Daptomycin Resistance in Corynebacterium striatum. mSphere 3:
Baumann-Dudenhoeffer, Aimee M; D'Souza, Alaric W; Tarr, Phillip I et al. (2018) Infant diet and maternal gestational weight gain predict early metabolic maturation of gut microbiomes. Nat Med 24:1822-1829
Crofts, Terence S; Wang, Bin; Spivak, Aaron et al. (2018) Shared strategies for ?-lactam catabolism in the soil microbiome. Nat Chem Biol 14:556-564
Potter, R F; Wallace, M A; McMullen, A R et al. (2018) blaIMP-27 on transferable plasmids in Proteus mirabilis and Providencia rettgeri. Clin Microbiol Infect 24:1019.e5-1019.e8
Crofts, Terence S; Gasparrini, Andrew J; Dantas, Gautam (2017) Next-generation approaches to understand and combat the antibiotic resistome. Nat Rev Microbiol 15:422-434
Crofts, Terence S; Wang, Bin; Spivak, Aaron et al. (2017) Draft Genome Sequences of Three ?-Lactam-Catabolizing Soil Proteobacteria. Genome Announc 5:
Potter, Robert F; D'Souza, Alaric W; Wallace, Meghan A et al. (2017) Draft Genome Sequence of the blaOXA-436- and blaNDM-1-Harboring Shewanella putrefaciens SA70 Isolate. Genome Announc 5:

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