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Title: Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing

Abstract

Francisella tularensis is classified as a Class A bioterrorism agent by the U.S. government due to its high virulence and the ease with which it can be spread as an aerosol. It is a facultative intracellular pathogen and the causative agent of tularemia. Ciprofloxacin (Cipro) is a broad spectrum antibiotic effective against Gram-positive and Gram-negative bacteria. Increased Cipro resistance in pathogenic microbes is of serious concern when considering options for medical treatment of bacterial infections. Identification of genes and loci that are associated with Ciprofloxacin resistance will help advance the understanding of resistance mechanisms and may, in the future, provide better treatment options for patients. It may also provide information for development of assays that can rapidly identify Cipro-resistant isolates of this pathogen. In this study, we then selected a large number of F. tularensis live vaccine strain (LVS) isolates that survived in progressively higher Ciprofloxacin concentrations, screened the isolates using a whole genome F. tularensis LVS tiling microarray and Illumina sequencing, and identified both known and novel mutations associated with resistance. For genes containing mutations encode DNA gyrase subunit A, a hypothetical protein, an asparagine synthase, a sugar transamine/perosamine synthetase and others. Finally, structural modeling performed on these proteinsmore » provides insights into the potential function of these proteins and how they might contribute to Cipro resistance mechanisms.« less

Authors:
 [1];  [2];  [1];  [2];  [2];  [1];  [1];  [1];  [3];  [3];  [1];  [4]
+ Show Author Affiliations
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical Life Sciences Directorate
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Computations Directorate
  3. Eureka Genomics, Hercules, CA (United States)
  4. Mayo Clinic, Phoenix, AZ (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1337000
Report Number(s):
LLNL-JRNL-698269
Journal ID: ISSN 1932-6203
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 11; Journal Issue: 9; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Jaing, Crystal J., McLoughlin, Kevin S., Thissen, James B., Zemla, Adam, Gardner, Shea N., Vergez, Lisa M., Bourguet, Feliza, Mabery, Shalini, Fofanov, Viacheslav Y., Koshinsky, Heather, Jackson, Paul J., and Wang, Junwen. Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing. United States: N. p., 2016. Web. doi:10.1371/journal.pone.0163458.
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Jaing, Crystal J., McLoughlin, Kevin S., Thissen, James B., Zemla, Adam, Gardner, Shea N., Vergez, Lisa M., Bourguet, Feliza, Mabery, Shalini, Fofanov, Viacheslav Y., Koshinsky, Heather, Jackson, Paul J., & Wang, Junwen. Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing. United States. https://doi.org/10.1371/journal.pone.0163458
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Jaing, Crystal J., McLoughlin, Kevin S., Thissen, James B., Zemla, Adam, Gardner, Shea N., Vergez, Lisa M., Bourguet, Feliza, Mabery, Shalini, Fofanov, Viacheslav Y., Koshinsky, Heather, Jackson, Paul J., and Wang, Junwen. Mon . "Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing". United States. https://doi.org/10.1371/journal.pone.0163458. https://www.osti.gov/servlets/purl/1337000.
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@article{osti_1337000,
title = {Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing},
author = {Jaing, Crystal J. and McLoughlin, Kevin S. and Thissen, James B. and Zemla, Adam and Gardner, Shea N. and Vergez, Lisa M. and Bourguet, Feliza and Mabery, Shalini and Fofanov, Viacheslav Y. and Koshinsky, Heather and Jackson, Paul J. and Wang, Junwen},
abstractNote = {Francisella tularensis is classified as a Class A bioterrorism agent by the U.S. government due to its high virulence and the ease with which it can be spread as an aerosol. It is a facultative intracellular pathogen and the causative agent of tularemia. Ciprofloxacin (Cipro) is a broad spectrum antibiotic effective against Gram-positive and Gram-negative bacteria. Increased Cipro resistance in pathogenic microbes is of serious concern when considering options for medical treatment of bacterial infections. Identification of genes and loci that are associated with Ciprofloxacin resistance will help advance the understanding of resistance mechanisms and may, in the future, provide better treatment options for patients. It may also provide information for development of assays that can rapidly identify Cipro-resistant isolates of this pathogen. In this study, we then selected a large number of F. tularensis live vaccine strain (LVS) isolates that survived in progressively higher Ciprofloxacin concentrations, screened the isolates using a whole genome F. tularensis LVS tiling microarray and Illumina sequencing, and identified both known and novel mutations associated with resistance. For genes containing mutations encode DNA gyrase subunit A, a hypothetical protein, an asparagine synthase, a sugar transamine/perosamine synthetase and others. Finally, structural modeling performed on these proteins provides insights into the potential function of these proteins and how they might contribute to Cipro resistance mechanisms.},
doi = {10.1371/journal.pone.0163458},
journal = {PLoS ONE},
number = 9,
volume = 11,
place = {United States},
year = {Mon Sep 26 00:00:00 EDT 2016},
month = {Mon Sep 26 00:00:00 EDT 2016}
}
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https://doi.org/10.1371/journal.pone.0163458
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In vitro antibiotic susceptibility of Francisella tularensis isolated from humans and animals
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Evolution toward high-level fluoroquinolone resistance in Francisella species
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journal, July 2003

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journal, July 2005

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  • Nucleic Acids Research, Vol. 33, Issue Web Server
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Structure of an ‘open’ clamp type II topoisomerase-DNA complex provides a mechanism for DNA capture and transport
journal, August 2013

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  • Nucleic Acids Research, Vol. 41, Issue 21
  • DOI: 10.1093/nar/gkt749

Genetic tools for highly pathogenic Francisella tularensis subsp. tularensis
journal, November 2006

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  • Microbiology, Vol. 152, Issue 11
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    Works referencing / citing this record:

    Francisella tularensis : FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation
    journal, January 2019

    Francisella tularensis : FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation
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    A Survey of Antimicrobial Resistance Determinants in Category A Select Agents, Exempt Strains, and Near-Neighbor Species
    journal, February 2020

    • Taitt, Chris R.; Leski, Tomasz A.; Chen, Amy
    • International Journal of Molecular Sciences, Vol. 21, Issue 5
    • DOI: 10.3390/ijms21051669
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