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Title: Evaluating the role of Burkholderia pseudomallei K96243 toxins BPSS0390, BPSS0395, and BPSS1584 in persistent infection

Abstract

Burkholderia pseudomallei is the causative agent of melioidosis, a disease with a mortality rate of up to 40% even with treatment. Despite the ability of certain antibiotics to control initial infection, relapse occurs in treated patients. The inability of antibiotics to clear this bacterial infection is in part due to persistence, an evasion mechanism against antibiotics and the effect of host defenses. Evaluation of antibiotic efficacy against B. pseudomallei revealed that up to 48% of in vitro grown populations can survive in a persister state. Toxin–antitoxin (TA) systems have been previously implicated in modulating bacterial persistence. Here, we generated three isogenic TA mutants and found that loss of each toxin gene did not alter antibiotic persistence or macrophage survival. In response to macrophage–induced persistence, all three toxin mutants demonstrated increased intracellular susceptibility to levofloxacin which in part was due to the inability of the mutants to induce persistence after nitric oxide or nutrient starvation. In an inhalational model of murine melioidosis, both ΔBPSS0395 and ΔBPSS1584 strains were attenuated, and treatment with levofloxacin led to significant reduction in lung colonisation and reduced splenic colonisation by ΔBPSS0395. Based on our findings, these toxins deserve additional evaluation as putative therapeutic targets.

Authors:
 [1]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [1]
  1. Univ. of Texas Medical Branch, Galveston, TX (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
Defense Threat Reduction Agency (DTRA); USDOE
OSTI Identifier:
1572326
Report Number(s):
LA-UR-19-21497
Journal ID: ISSN 1462-5814
Grant/Contract Number:  
89233218CNA000001
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Cellular Microbiology
Additional Journal Information:
Journal Volume: 21; Journal Issue: 12; Journal ID: ISSN 1462-5814
Publisher:
Wiley
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science; Burkholderia pseudomallei; melioidosis; persistence; toxin-antitoxin; chronic infection

Citation Formats

Ross, Brittany N., Micheva‐Viteva, Sofiya N., Hong‐Geller, Elizabeth, and Torres, Alfredo G. Evaluating the role of Burkholderia pseudomallei K96243 toxins BPSS0390, BPSS0395, and BPSS1584 in persistent infection. United States: N. p., 2019. Web. doi:10.1111/cmi.13096.
Ross, Brittany N., Micheva‐Viteva, Sofiya N., Hong‐Geller, Elizabeth, & Torres, Alfredo G. Evaluating the role of Burkholderia pseudomallei K96243 toxins BPSS0390, BPSS0395, and BPSS1584 in persistent infection. United States. doi:10.1111/cmi.13096.
Ross, Brittany N., Micheva‐Viteva, Sofiya N., Hong‐Geller, Elizabeth, and Torres, Alfredo G. Sat . "Evaluating the role of Burkholderia pseudomallei K96243 toxins BPSS0390, BPSS0395, and BPSS1584 in persistent infection". United States. doi:10.1111/cmi.13096. https://www.osti.gov/servlets/purl/1572326.
@article{osti_1572326,
title = {Evaluating the role of Burkholderia pseudomallei K96243 toxins BPSS0390, BPSS0395, and BPSS1584 in persistent infection},
author = {Ross, Brittany N. and Micheva‐Viteva, Sofiya N. and Hong‐Geller, Elizabeth and Torres, Alfredo G.},
abstractNote = {Burkholderia pseudomallei is the causative agent of melioidosis, a disease with a mortality rate of up to 40% even with treatment. Despite the ability of certain antibiotics to control initial infection, relapse occurs in treated patients. The inability of antibiotics to clear this bacterial infection is in part due to persistence, an evasion mechanism against antibiotics and the effect of host defenses. Evaluation of antibiotic efficacy against B. pseudomallei revealed that up to 48% of in vitro grown populations can survive in a persister state. Toxin–antitoxin (TA) systems have been previously implicated in modulating bacterial persistence. Here, we generated three isogenic TA mutants and found that loss of each toxin gene did not alter antibiotic persistence or macrophage survival. In response to macrophage–induced persistence, all three toxin mutants demonstrated increased intracellular susceptibility to levofloxacin which in part was due to the inability of the mutants to induce persistence after nitric oxide or nutrient starvation. In an inhalational model of murine melioidosis, both ΔBPSS0395 and ΔBPSS1584 strains were attenuated, and treatment with levofloxacin led to significant reduction in lung colonisation and reduced splenic colonisation by ΔBPSS0395. Based on our findings, these toxins deserve additional evaluation as putative therapeutic targets.},
doi = {10.1111/cmi.13096},
journal = {Cellular Microbiology},
issn = {1462-5814},
number = 12,
volume = 21,
place = {United States},
year = {2019},
month = {8}
}

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