# Project 3

> **NIH NIH P20** · MIRIAM HOSPITAL · 2020 · $361,248

## Abstract

Project Summary 
 The development and spread of antibiotic resistance is jeopardizing the efficacy of our current antibiotic 
arsenal. To formulate targeted therapies that make better use of existing antibiotics and reduce the development 
of resistance, we must understand how antibiotics impact both the pathogenic and beneficial members of the 
human microbiome. This is particularly important because the disruption of microbiome homeostasis by 
antibiotics is associated with multiple microbiome-related diseases, such as Clostridium difficile-associated 
diarrhea and inflammatory bowel disease. Current descriptive microbiome research, focused on identifying 
taxonomic changes, has not addressed the mechanistic question of why specific bacteria within a microbial 
community are negatively impacted by antibiotics while others are not. The work proposed here will move past 
this limitation by transcriptionally profiling the impacts of antibiotics on the total microbial community in vivo to 
provide functional and mechanistic insight into the action of antibiotics in the microbiome. The central hypothesis 
of this study is that the induction of tolerance and resistance mechanisms mediates toxicity to antibiotic exposure 
in susceptible members of the microbiome. This proposal is focused on tolerance mechanisms related to the 
metabolic state of bacteria before and during treatment. The microbiome consists of many metabolic 
microenvironments and within these communities metabolically active bacteria are likely to be more susceptible 
than less active species. Total transcriptional profiles of the microbiome can be used to study the roles of well- 
defined tolerance and resistance mechanisms within the microbiome in vivo. This project will test our central 
hypothesis in three aims: Aim 1) Determine the impacts of broad-spectrum antibiotics on the structure of the 
salivary microbiome derived from clinical samples. Aim 2) Determine the total transcriptional response of the 
microbiome to bactericidal and bacteriostatic antibiotic therapy. Aim 3) Profile the impacts of ciprofloxacin on the 
structure and function of the murine microbiome in conjunction with host metabolic perturbation. In addition to 
testing this hypothesis, a key goal of this exploratory proposal is to implement a novel outpatient-based 
methodology to study the response of the human microbiome to antibiotic therapy. The ultimate goal of this work 
is to provide information about the impact of antibiotic therapy on the structure and function of the microbiome, 
in order to allow clinicians to select therapies that minimize microbiome-related complications and the transfer 
and development of resistance. This basic knowledge will help clinicians to improve antibiotic therapy by 
promoting evidence-based, targeted treatments to safeguard our current arsenal of antibiotics.

## Key facts

- **NIH application ID:** 9999631
- **Project number:** 5P20GM121344-03
- **Recipient organization:** MIRIAM HOSPITAL
- **Principal Investigator:** Peter Belenky
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,248
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999631

## Citation

> US National Institutes of Health, RePORTER application 9999631, Project 3 (5P20GM121344-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9999631. Licensed CC0.

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