# Self-assembly of 2D metallo-supramolecules as a novel class of antimicrobial biomaterials via forming transmembrane channels

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $283,595

## Abstract

Antibiotic resistance has attracted increasing public attention in recent years, owing to the occurrence of
multidrug-resistant bacterial strains. The World Health Organization identified antimicrobial resistance as one
of the three greatest threats facing mankind in the 21st century. Therefore, there is an urgent need to develop
new antibiotics with unconventional molecular approaches on fighting bacterial infections and drug-resistance.
Daptomycin as the first clinically approved lipopeptide antibiotic is notably active against multidrug-resistant
pathogens. The consensus mechanism of daptomycin involves disruption of the bacterial cell membrane by
forming transmembrane channels, which allows the flow of ions out of the cell and lead to the depolarization of
the membrane and cell death. As the membrane interaction doesn't involve specific cellular or membrane
targets, the probability of resistance development in bacteria is minimal. Inspired by daptomycin, several
diverse families of synthetic, membrane-active macromolecules were developed to form channels within
membrane bilayers. Despite significant enthusiasm, there are intrinsic drawbacks associated with these
synthetic systems, including low-to-moderate activity, high cellular toxicity, and inconvenient optimization. In
our preliminary study, supramolecular concentric hexagons displayed high antimicrobial activity against Gram-
positive pathogens and negligible toxicity to eukaryotic cells through forming transmembrane channels.
Compared to daptomycin, the synthesis is easier for scaling up and the large surface area of supramolecules
allows effective interaction with bacterial membrane to ensure channel forming. These findings may pave a
new avenue in the seeking of the new generation of antimicrobial agents. Our long-term goal is to develop a
new class of supramolecules with novel mechanisms in the treatment of bacterial infectious disease. The
objective is to identify more potent analogs of supramolecules, and to investigate their mechanism of action on
bacterial membranes. Our central hypothesis is that those 2D supramolecules can assemble into channels with
multi-layered structure and distinct pore size inside the bacterial membrane and thus, lead to the leakage of
cytoplasmic components and cell death. As such, we propose to accomplish the following specific aims: (1)
Design and synthesize novel analogs of previously designed antimicrobial 2D multi-layered metallo-
supramolecules; (2) Through structure-function-relationship studies, identify lead supramolecules with specific
activity against Gram-positive bacteria; (3) Investigate if forming multilayered channels with distinct pore size in
the bacterial membrane is the general bactericidal mechanism. We contend that our work will have a major
positive impact, as these studies are highly likely to provide a new class of antibiotic agents with
unprecedented mechanisms. In addition, the research will demonstrate the biological potential...

## Key facts

- **NIH application ID:** 9882282
- **Project number:** 5R01GM128037-03
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Jianfeng Cai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $283,595
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882282

## Citation

> US National Institutes of Health, RePORTER application 9882282, Self-assembly of 2D metallo-supramolecules as a novel class of antimicrobial biomaterials via forming transmembrane channels (5R01GM128037-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9882282. Licensed CC0.

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