Antibiotic-resistant bacterial infections are a major and increasing problem in US hospitals. Among antibiotic resistant bacterial pathogens, Vancomycin-Resistant Enterococcus (VRE) is emerging as a leading cause of blood-stream infections, particularly in patients receiving treatment for cancer or following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our studies demonstrated that VRE dominates the intestinal microbiota of patients being treated with antibiotics. We have also demonstrated that introduction of a normal microbiota into VRE-dominated mice eliminate VRE carriage. The overall goal of this application is to identify commensal bacteria in mice and humans that confer resistance to intestinal colonization by VRE and to identify mechanisms of VRE-specific colonization resistance. We have established a bank of bacterial strains that, in aggregate, confer resistance to VRE, and will use these strains to identify strain combinations that provide complete colonization resistance.
Our second aim i s to characterize mechanisms of VRE clearance by protective commensal microbes and to test the hypothesis that innate immune activation and microbiota-mediated modification of the metabolome synergize to reduce VRE density in the gut. Our preliminary data demonstrate that secondary bile salts strongly inhibit VRE growth and our experiments will determine whether loss of secondary bile salts enables VRE to achieve a state of domination in the cecum.
The third aim i s to transfer banked fecal microbiota from allo-HSCT patients who were susceptible or resistant to VRE intestinal domination into germ-free mice to identify bacterial strains from the human microbiota that confer resistance to VRE colonization and/or domination. These studies are addressing the growing problem of antibiotic resistance in an era where the prospects for further antibiotic development are dim. Identifying commensal bacteria that provide resistance to infection by antibiotic- resistant pathogens and determining mechanisms of VRE clearance may lead to more effective approaches to reduce infections and patient-to-patient transmission.

Public Health Relevance

Infections caused by antibiotic-resistant bacteria are an increasing problem in the US, with an alarming frequency in patients requiring hospitalization for cancer treatment. Antibiotic development has been insufficient to deal with this problem, but recent studies show normal commensal bacteria in the intestine can provide a remarkable degree of resistance to infection. The experiments described in this application will identify commensal bacterial strains that confer high-level resistance to antibiotic-resistant bacteria with the goal of reducing infections and limiting transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042135-19
Application #
9178052
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Huntley, Clayton C
Project Start
1998-06-01
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
19
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Lewis, Brittany B; Carter, Rebecca A; Pamer, Eric G (2016) Bile acid sensitivity and in vivo virulence of clinical Clostridium difficile isolates. Anaerobe 41:32-36
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Becattini, Simone; Taur, Ying; Pamer, Eric G (2016) Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. Trends Mol Med 22:458-78

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