# Predictive Guidelines for Penetrance and Discovery of Broad-Spectrum Antibiotics

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $1,140,875

## Abstract

PROJECT SUMMARY/ABSTRACT
The percent of Gram-negative bacterial infections that are resistant to common antibiotics has increased at an
alarming rate over the last decade, and there is now an acute need for the discovery of novel antibiotics effective
against multidrug-resistant Gram-negative pathogens. The standard method of antibacterial discovery – whole-
cell screening of compound collections – has met with repeated failure for Gram-negatives, and these failures
have been traced to the fact that very few compounds in standard collections can penetrate the Gram-negative
cell membranes and accumulate in these pathogens. Unfortunately, there has been scant information about the
types of compounds that are competent for accumulation in Gram-negatives. Excitingly, we recently assessed a
unique collection of >180 diverse compounds for their ability to accumulate in E. coli, trained a random forest
classification model to analyze the results, and from this data we identified physicochemical properties important
for accumulation and developed predictive guidelines for compound accumulation in E. coli. We then showed
the utility of these guidelines by converting a Gram-positive-only antibiotic into a broad-spectrum agent. We now
propose to develop tools that will allow us to fully define the physicochemical traits that enable compounds
accumulation in three of the most concerning Gram-negative bacteria, carbapenem-resistant
Enterobacteriaceae (CRE), drug-resistant Acinetobacter, and drug-resistant P. aeruginosa (to be referred to
collectively as EAP pathogens). Specifically, we seek to develop novel tools in the area of chemical probes
(compound collections), bacterial strains, and computational models. Using these tools in conjunction with our
well-validated compound accumulation assay, we intend to define the physicochemical traits needed for
compound accumulation in the EAP pathogens, including assessment of the influence of porins and efflux
pumps, and the relative contribution of the outer and inner-membranes to blocking compound penetrance. Our
predictive guidelines will be utilized to convert several high-value Gram-positive-only compounds into broad-
spectrum antibiotics.

## Key facts

- **NIH application ID:** 10326787
- **Project number:** 5R01AI136773-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Paul Hergenrother
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,140,875
- **Award type:** 5
- **Project period:** 2018-02-06 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326787

## Citation

> US National Institutes of Health, RePORTER application 10326787, Predictive Guidelines for Penetrance and Discovery of Broad-Spectrum Antibiotics (5R01AI136773-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10326787. Licensed CC0.

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