# Optimization of efflux avoidance and inhibition for antibiotic development

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA · 2020 · $1,048,793

## Abstract

Project Summary
Failures of antibiotic therapy occur with increasing frequency in clinics due to the spread of multidrug resistant
bacterial pathogens. The major challenge are infections caused by Gram-negative bacteria that are protected
from antibiotics by the concerted action of multidrug efflux pumps and the low permeability barrier of outer
membranes. Pseudomonas aeruginosa, an opportunistic human pathogen responsible for a variety of infectious
diseases, is notorious for its antibiotic impermeability. A handful of clinical antibiotics used against this pathogen
are beginning to fail due to the emergence of multidrug resistant strains. New antibiotics are needed to address
this growing threat.
Decades of antibiotic discovery and optimization perfected empirical approaches for improvement of antibiotic
action and avoidance of class-specific resistance mechanisms. The current critical challenge is to develop
approaches that will enable antibiotic penetration across non-specific permeability barriers of Gram-negative
bacteria, which present an urgent and serious threat to public health. This project responds to this challenge and
proposes the development of a new technology for optimization of efflux avoidance and inhibition in clinical and
investigational antibacterial agents that will be effective against Gram-negative bacteria.
The proposed approach targets simultaneously the multidrug efflux mechanism of P. aeruginosa and its outer
membrane barrier and combines cutting edge technologies in experimental analyses of efflux inhibition and drug
penetration, kinetic modeling of drug accumulation, computer simulations of drug efflux and transmembrane
diffusion, synthetic chemistry and machine learning analyses. The central objective of the proposal is to create
a mechanism-based predictive model that integrates physicochemical properties of compounds, kinetics of their
intracellular accumulation and transmembrane diffusion, and a molecular level description of the interaction of
efflux transporters with their substrates and inhibitors. The model will be validated by focused medicinal
chemistry efforts to generate antibacterial agents that combine the traits of effective antibiotics and potent efflux
pump inhibitors or avoiders.
This multi-disciplinary approach is enabled by the collaborative efforts of PIs on the project: Helen Zgurskaya
(biochemistry of drug uptake and efflux), Valentin Rybenkov (kinetic modeling), Paolo Ruggerone (computational
biophysics of efflux), Gnanakaran (computational simulations of membrane permeation) and John Walker
(medicinal chemistry).

## Key facts

- **NIH application ID:** 9853719
- **Project number:** 5R01AI136799-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA
- **Principal Investigator:** Sandrasegaram Gnanakaran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,048,793
- **Award type:** 5
- **Project period:** 2018-02-07 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853719

## Citation

> US National Institutes of Health, RePORTER application 9853719, Optimization of efflux avoidance and inhibition for antibiotic development (5R01AI136799-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9853719. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*