# Exploring mechanical mechanisms of antibiotic resistance

> **NIH NIH R35** · NEW YORK UNIVERSITY · 2021 · $322,616

## Abstract

Summary
Traditionally, studies of antibiotic resistance have focused on evolutionary and molecular
mechanisms of resistance. However, many of our best antibiotics target the bacterial cell envelope,
which is a mechanically robust, structural exoskeleton for the cell. Ultimately, these antibiotics cause
cell death by weakening the envelope enough to cause explosion of the cell by the large, hydrostatic
pressure within it. Despite the central mechanical importance of the cell envelope, we have little
understanding of which molecules and moieties within it are critical for its load-bearing capacity.
Addressing this question would transform our understanding of antibiotic resistance. A primary
reason for this gap in our knowledge is the formidable challenge of applying mechanical forces to
single bacterial cells while monitoring their physiology. The proposed research will address this
obstacle by applying innovative, highly precise, high-throughput microfluidics and microscopy-based
assays to measure the mechanical properties of two of the major cell envelope components in
bacteria, the outer membrane and the cell wall. These assays will be combined with molecular and
cell biological techniques, and biophysical theory, to explore an emerging paradigm within
microbiology: that bacteria control antibiotic resistance by adaptively tuning the mechanical properties
of their cell envelope. First, building on the recent landmark finding that the outer membrane confers
antibiotic resistance to bacteria because of its mechanical strength, the dependence of outer
membrane stiffness and mechanical antibiotic resistance on the fine-scale biochemical composition of
the outer membrane will be systematically measured. Next, the mechanism of outer membrane
vesiculation (a process underlying antibiotic resistance and pathogenesis) will be investigated by
combining a theoretical mechanical model of vesiculation with novel microscopy assays to quantify
vesiculation dynamics, while genetically tuning protein-protein interactions between the cell wall and
outer membrane. Finally, the scope of these studies will be extended to Gram-positive bacteria by
determining the dependence of antibiotic resistance on cell wall stiffness in these species, specifically
focusing on the mechanical contributions of teichoic acids to resistance. Together, these studies will
transform our understanding of bacterial pathogen survival and growth, and point to fresh strategies
to circumvent antibiotic resistance and treat bacterial infections.

## Key facts

- **NIH application ID:** 10276887
- **Project number:** 1R35GM143057-01
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Enrique Rojas
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $322,616
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276887

## Citation

> US National Institutes of Health, RePORTER application 10276887, Exploring mechanical mechanisms of antibiotic resistance (1R35GM143057-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10276887. Licensed CC0.

---

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