# Characterizing the role of antimicrobial peptide resistance in plague transmission

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $381,250

## Abstract

PROJECT SUMMARY
It is difficult to overstate the impact Yersinia pestis, the bacterial agent of plague, has had on human history. It is of
great concern as a potential agent of bioterrorism because of its highly virulent nature, and it consistently infects
thousands of people per year in endemic foci around the world, including the southwestern United States. Despite
these facts, there is much that is unknown about the ability of Y. pestis to infect both flea vectors and mammalian
hosts, and its ability to undergo successful transmission between them. The goal of this project is to determine the
genetic and molecular mechanisms of resistance to cationic antimicrobial peptides (CAMPs) in Y. pestis, and the role
this resistance plays in allowing it to successfully infect fleas. Data from our lab revealed that numerous Y. pestis
transposon mutants that were unable to maintain successful flea infections also showed in vitro hypersensitivity to
CAMPs. Two mutants contained insertions in genes predicted to block modification of the outer membrane
lipopolysaccharide, and we recently published data that this was in fact the cause of the mutants' CAMP sensitivity.
Several mutations however were in novel or hypothetical genes not previously known to be involved in CAMP
resistance. Additionally, disruption of genes involved in biosynthesis of the enterobacterial common antigen resulted
in unexpected CAMP-susceptibility in Y. pestis by an unknown mechanism. These data, along with the recent
discovery of the plasmid-mediated mcr colistin resistance genes, indicate that CAMP resistance is more complex,
and less well understood, than previously thought.
 The first specific aim of this project is to investigate structural and genetic changes present in these CAMP-
susceptible mutants to improve our understanding of the mechanisms of CAMP resistance. Since CAMPs, such as
polymyxins, are often one of the only classes of antibiotics with activity against multi-drug resistant bacterial
infections, identifying novel mechanisms of resistance is of critical importance. The second specific aim involves
constructing a comprehensive, ordered transposon mutant library of all non-essential genes in Y. pestis KIM6+. This
library will be screened for mutants that are susceptible to structurally diverse CAMPs in order to identify additional
and potentially novel mechanisms of resistance. Mutants identified in this screen will be analyzed using the
biophysical and genetic approaches from the first aim to elucidate their mechanisms of CAMP resistance. The third
specific aim is to determine the potential role of different mechanisms of CAMP resistance in transmission by testing
the ability of the mutants to maintain infection, and by determining the distribution of mutants in a natural flea
vector. The knowledge obtained from this project on CAMP resistance mechanisms will open up a number of new
trajectories in plague and antimicrobial resistance research, and the ordered mutant...

## Key facts

- **NIH application ID:** 9901450
- **Project number:** 5R01AI130255-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Mark A Fisher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2017-05-12 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901450

## Citation

> US National Institutes of Health, RePORTER application 9901450, Characterizing the role of antimicrobial peptide resistance in plague transmission (5R01AI130255-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9901450. Licensed CC0.

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