# Mechanisms of Allostery and Molecular Recognition in the Small Multidrug Resistance Family

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2022 · $453,581

## Abstract

Project Summary
 Bacterial drug resistance is a worldwide problem that limits the effectiveness of antibiotics in the clinic. While
there are several molecular mechanisms that contribute to drug resistant phenotypes, it is well established that
efflux pumps play a prominent role in pathogenic bacteria. Indeed, multidrug transporters constitute a
fundamental mechanism used by bacteria to survive in the presence of toxic compounds by binding and
transporting a broad array of structurally diverse compounds. The long-term goals of this project are to discover
novel mechanisms used by multidrug transporters and to harness this knowledge to predict and control function.
In this competitive renewal, we are now poised to tackle the major challenge in the field of understanding how
efflux pumps achieve broad drug specificity required for conferring multidrug resistance. To accomplish this goal,
we need to establish a comprehensive understanding of the catalytic cycle for an efflux pump system amenable
to detailed biological, biochemical and biophysical studies. For this reason, our proposal will use EmrE from the
SMR family as the model drug transporter since it embodies the minimal level of complexity while retaining the
key features shared among all secondary active efflux pumps. Aim 1 will test an occluded-state theory that we
hypothesize is widely used by efflux pumps for drug binding. Aim 2 will seek to define the molecular basis for
substrate-induced activation of dynamics versus inhibitor-induced repression of dynamics, as well as
development of a computational platform for predicting binding and transport. Finally, Aim 3 will set out to
determine the molecular basis of binding specificity versus promiscuity through a comparative analysis of two
subfamilies within the SMR family that have markedly different specificity profiles. Each of these Aims works
synergistically toward our long-term goal of articulating novel transport mechanisms and applying our knowledge
to develop models for making predictions about function. A major strength of this project is the integrated nature
of the approach which utilizes significant collaboration and a combination of biological, biophysical, and
computational methods aimed at unveiling general transport mechanisms designed by nature and shared among
other multidrug efflux pumps. The outcomes of this research will make a significant impact in understanding
efflux-mediated multidrug resistance, and the approaches and methods developed will be translatable to
knowledge discovery in other efflux systems.

## Key facts

- **NIH application ID:** 10451577
- **Project number:** 5R01AI108889-08
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Nathaniel J. Traaseth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,581
- **Award type:** 5
- **Project period:** 2014-07-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451577

## Citation

> US National Institutes of Health, RePORTER application 10451577, Mechanisms of Allostery and Molecular Recognition in the Small Multidrug Resistance Family (5R01AI108889-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10451577. Licensed CC0.

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