Intracellular Experimental Evolution of Francisella tularensis Subsp. holarctica Live Vaccine Strain (LVS) to Antimicrobial Resistance

dc.citation.firstpage308en_US
dc.citation.issueNumber2en_US
dc.citation.journalTitleACS Infectious Diseasesen_US
dc.citation.lastpage321en_US
dc.citation.volumeNumber9en_US
dc.contributor.authorMehta, Heer H.en_US
dc.contributor.authorSong, Xinhaoen_US
dc.contributor.authorShamoo, Yousifen_US
dc.date.accessioned2023-02-20T17:17:48Zen_US
dc.date.available2023-02-20T17:17:48Zen_US
dc.date.issued2023en_US
dc.description.abstractIn vitro experimental evolution has complemented clinical studies as an excellent tool to identify genetic changes responsible for the de novo evolution of antimicrobial resistance. However, the in vivo context for adaptation contributes to the success of particular evolutionary trajectories, especially in intracellular niches where the adaptive landscape of virulence and resistance are strongly coupled. In this work, we designed an ex vivo evolution approach to identify evolutionary trajectories responsible for antibiotic resistance in the Live Vaccine Strain (LVS) of Francisella tularensis subsp. holarctica while being passaged to increasing ciprofloxacin (CIP) and doxycycline (DOX) concentrations within macrophages. Overall, adaptation within macrophages advanced much slower when compared to previous in vitro evolution studies reflecting a limiting capacity for the expansion of adaptive mutations within the macrophage. Longitudinal genomic analysis identified resistance conferring gyrase mutations outside the Quinolone Resistance Determining Region. Strikingly, FupA/B mutations that are uniquely associated with in vitro CIP resistance in Francisella were not observed ex vivo, reflecting the coupling of intracellular survival and resistance during intracellular adaptation. To our knowledge, this is the first experimental study demonstrating the ability to conduct experimental evolution to antimicrobial resistance within macrophages. The results provide evidence of differences in mutational profiles of populations adapted to the same antibiotic in different environments/cellular compartments and underscore the significance of host mediated stress during resistance evolution.en_US
dc.identifier.citationMehta, Heer H., Song, Xinhao and Shamoo, Yousif. "Intracellular Experimental Evolution of Francisella tularensis Subsp. holarctica Live Vaccine Strain (LVS) to Antimicrobial Resistance." <i>ACS Infectious Diseases,</i> 9, no. 2 (2023) American Chemical Society: 308-321. https://doi.org/10.1021/acsinfecdis.2c00483.en_US
dc.identifier.doihttps://doi.org/10.1021/acsinfecdis.2c00483en_US
dc.identifier.urihttps://hdl.handle.net/1911/114465en_US
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.en_US
dc.subject.keywordintracellular experimental evolutionen_US
dc.subject.keywordantimicrobial resistanceen_US
dc.subject.keywordex vivoen_US
dc.subject.keywordFrancisellaen_US
dc.subject.keywordwhole genome sequencing analysisen_US
dc.titleIntracellular Experimental Evolution of Francisella tularensis Subsp. holarctica Live Vaccine Strain (LVS) to Antimicrobial Resistanceen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Mehta_etal_ACS_Infectious_Disease_2023.pdf
Size:
1.05 MB
Format:
Adobe Portable Document Format
Description: