# Mechanical Regulation of Ultra-Sensitivity in E. Coli Flagellar Motors

> **NIH NIH R01** · TEXAS ENGINEERING EXPERIMENT STATION · 2020 · $282,460

## Abstract

PROJECT ABSTRACT
 Swarming motility, exhibited by many motile species of bacteria, has been implicated in the rapid invasion
of hosts during urinary tract infections (UTIs). Annually, UTIs result in several thousand deaths in the US alone
and represent a significant load on the public healthcare system. Swarming motility is substrate-associated and
is driven by bacterial flagellar motors that rotate extracellular, helical filaments to generate thrust on the cell-
body. Although chemotaxis is not required for swarming, the functioning of a molecular switch that enables
reversals in the direction of motor-rotation is indispensable. The switch is activated by CheY-P, an intracellular
response-regulator that is regulated by the chemotaxis network. Upon CheY-P-binding, cooperative
interactions within the multi-subunit switch-complex drive concerted transitions from counterclockwise (CCW)
to clockwise (CW) conformations with increasing likelihood, resulting in changes in the direction of rotation. Our
recent results indicate that flagellar motors sense mechanical forces, arising from contact with solid substrates,
and that leads to the inhibition of switching. In a short time the motor adapts to these forces and recovers the
ability to reverse directions. However, the molecular underpinnings responsible for adaptation remain unclear.
Thus, there is a critical need to determine how the switch adapts to mechanical stimuli to promote swarming.
Without such knowledge, the potential to capitalize on antivirulence strategies as therapeutic approaches to
combat swarming-mediated host-invasion and antibiotic resistance will likely remain limited. Our long-term goal
is to contribute toward the development of new clinically useful antivirulence strategies that target bacterial
swarming and colonization. Our overall objective in this application is to determine the molecular mechanisms
whereby the switch adapts perfectly to mechanical signals and promotes swarming. Our central hypothesis is
that motor-mechanosensing (sensing of mechanical signals) results in the tuning of ultra-sensitivity through the
modulation of allosteric and cooperative interactions within the switch. The rationale for the proposed work is
that a determination of the mechanism of mechanical control of ultra-sensitivity is likely to provide a conceptual
framework for the development of strategies to interfere with switch adaptation, and to mitigate swarming. At
the completion of the proposed research, it is our expectation to have quantitatively explained the mechanisms
underlying switch-adaptation and modulation of ultra-sensitivity by mechanical forces. Results are expected to
have an important positive impact because a detailed understanding of switching near substrates will provide a
strong foundation for novel substrate-design in biomedical devices, including catheters, which will target the
motor-switch to inhibit swarming.

## Key facts

- **NIH application ID:** 10002253
- **Project number:** 5R01GM123085-04
- **Recipient organization:** TEXAS ENGINEERING EXPERIMENT STATION
- **Principal Investigator:** Pushkar Prakash Lele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $282,460
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002253

## Citation

> US National Institutes of Health, RePORTER application 10002253, Mechanical Regulation of Ultra-Sensitivity in E. Coli Flagellar Motors (5R01GM123085-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10002253. Licensed CC0.

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