# Exploitation of multiple heteroresistance for effective antibiotic combination therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $803,714

## Abstract

Project Summary/Abstract
Antibiotic resistance is one of the most serious medical challenges of our time. This crisis puts patients at risk
of untreatable bacterial infections and threatens major advances of modern medicine that rely on antibiotics
(transplants, chemotherapy, etc). There are at least 2 million antibiotic resistant infections each year in the US,
leading to over 23,000 deaths. It is estimated that without significant action, worldwide annual mortality due to
these infections will reach 10 million by 2050, surpassing the predicted mortality from cancer. Unfortunately,
some bacteria, including specific isolates of carbapenem-resistant Enterobacteriaceae (CRE) and
carbapenem-resistant Acinetobacter baumannii (CRAB), are now resistant to all available antibiotics and are
essentially untreatable. In such instances, combinations of antibiotics are employed to try to overcome the
resistance to individual drugs, but are only sporadically effective. When and why combinations work is unclear,
and clinicians therefore lack a sound scientific rationale for choosing antibiotics to include in these regimens.
Our research has revealed an unexpected principle, distinct from antibiotic synergy, that can be used
to design personalized combinations to kill clinical bacterial isolates including pan-resistant strains.
This combination therapy approach is based on heteroresistance, an enigmatic form of antibiotic resistance in
which a bacterial isolate harbors a resistant subpopulation that can rapidly replicate in the presence of an
antibiotic, while the majority susceptible population is killed. However, we now show that when combined, two
antibiotics to which a given strain is heteroresistant, kill the bacteria as each drug inhibits the subpopulation of
cells resistant to the other [Band et al, Nature Microbiology, 2019]. Thus, heteroresistance towards multiple
antibiotics (“multiple heteroresistance”) can be exploited as a bacterial Achilles' heel and the basis of effective
combination regimens. Importantly, this method employs existing FDA-approved antibiotics and can be
employed in the clinic immediately. This paradigm-shifting approach to combination therapy has the
potential to have a major translational impact, but must first be broadly and thoroughly interrogated. Here, we
propose to use a robust set of CRE and CRAB clinical isolates from a Georgia-based surveillance initiative to
test for heteroresistance to a wide range of antibiotics. This will allow the selection and in vitro and in vivo
testing of combinations targeting multiple heteroresistance. We will further study the relationship between the
resistant subpopulations in multiple heteroresistant isolates, as well as performing dynamic flow experiments to
determine the pharmacokinetics and pharmacodynamics of effective combinations. This research has the
potential to provide clinicians with a rational and predictable method with which to prescribe effective antibiotic
combinations to t...

## Key facts

- **NIH application ID:** 10206015
- **Project number:** 5R01AI148661-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** DAVID S WEISS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $803,714
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206015

## Citation

> US National Institutes of Health, RePORTER application 10206015, Exploitation of multiple heteroresistance for effective antibiotic combination therapy (5R01AI148661-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10206015. Licensed CC0.

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