# Defining Parameters for Compound Accumulation in Gram-Negative Pathogens

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $265,608

## Abstract

Project Summary/Abstract
Infections caused by Gram-negative bacterial pathogens are on the rise in hospital and non-hospital
settings. Indeed 4 of the 6 “ESKAPE” pathogens – recently highlighted as responsible for the majority of
hospital infections and being exceedingly difficult to treat – are Gram-negatives. The development of new
antibiotics is complicated by the fact that Gram-negative bacteria have a highly impenetrable membrane
that confers significant intrinsic resistance to antibacterial agents. Without advances, we will soon face a
crisis situation whereby our current antibiotics can no longer effectively treat these infections. Although it
is clear that novel antibiotics for Gram-negative infections are desperately needed, there has been minimal
progress in this regard, and it has been over 50 years since a new class of drugs have been introduced
for Gram-negative pathogens. Why is this? A chief reason is that no rules or guidelines have been
developed that enable the accurate prediction of compound accumulation in Gram-negatives, thus it has
been difficult to convert Gram-positive-only drugs into broad-spectrum agents, and impossible to create
large collections of compounds that are biased for Gram-negative accumulation. We have been working
to define the physicochemical features of small molecules that allow them to accumulate in E. coli. In
important preliminary results we have assessed >180 diverse compounds for their ability to accumulate
in E. coli; using a sophisticated computation analysis of the data, we have begun to discern the
physicochemical traits that govern compound accumulation in E. coli, and we have used these guidelines
to convert a Gram-positive-only antibiotic into one that also has activity against many Gram-negative
pathogens. We now propose to gain a further understanding of compound accumulation in E. coli
(especially with respect to porin penetration and pump-mediated efflux), and to extend these guidelines
to other Gram-negative pathogens. We will also use the guidelines to convert important FDA-approved
antibiotics that are currently only effective against Gram-positive bacteria into derivatives that are also
active against Gram-negative organisms. Finally, we will use our guidelines to design and construct a
collection of thousands of compounds all of which are heavily biased for accumulation in Gram-negative
bacteria. Significant outputs of this work include a fundamental understanding of the types of compounds
that accumulate in Gram-negative bacteria, and actionable guidelines to be used to discover novel
antibacterials.

## Key facts

- **NIH application ID:** 9933932
- **Project number:** 5R01GM118575-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Paul Hergenrother
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $265,608
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933932

## Citation

> US National Institutes of Health, RePORTER application 9933932, Defining Parameters for Compound Accumulation in Gram-Negative Pathogens (5R01GM118575-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9933932. Licensed CC0.

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