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Title: Increased mortality in mice following immunoprophylaxis therapy with high dosage of nicotinamide in Burkholderia persistent infections

Bacterial persistence, known as non-inherited antibacterial resistance, is a contributing factor to the establishment of long-lasting chronic bacterial infections. In this study, we examined the ability of nicotinamide (NA) to potentiate different classes of antibiotics against Burkholderia thailandensis persister cells. Here we demonstrate that addition of NA in in vitro models of B. thailandensis infection resulted in a significant depletion of the persister population in response to various classes of antibiotics. We applied microfluidic bioreactors with a continuous media flow to study the effect of supplementation with a NA gradient on the recovery of B. thailandensis persister populations. A co-culture of human neutrophils pre-activated with 50 µM NA and B. thailandensis resulted in the most efficient reduction in the persister population. Applying single cell RNA FISH analysis and quantitative PCR, we found that NA inhibited gene expression of the stringent response regulator relA, implicated in the regulation of the persister metabolic state. In conclusion, we also demonstrate that a therapeutic dose of NA (250mg/kg), previously applied as immunoprophylaxis against antibiotic-resistant bacterial species, produced adverse effects in an in vivo murine infection model of the highly pathogenic Burkholderia pseudomallei, indicating that therapeutic dose and metabolite effects have to be carefully evaluatedmore » and tailored for every case of potential clinical application.« less
Authors:
ORCiD logo [1] ;  [2] ;  [1] ; ORCiD logo [1] ;  [1] ; ORCiD logo [1] ;  [3] ; ORCiD logo [1] ;  [2] ; ORCiD logo [1]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Univ. of Texas Medical Branch, Galveston, TX (United States)
  3. Univ. of New Mexico Health Sciences Center, Albuquerque, NM (United States)
Publication Date:
Report Number(s):
LA-UR-18-26923
Journal ID: ISSN 0019-9567
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Infection and Immunity
Additional Journal Information:
Journal Volume: 87; Journal Issue: 1; Journal ID: ISSN 0019-9567
Publisher:
American Society for Microbiology
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
Defense Threat Reduction Agency (DTRA); USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1480049

Micheva-Viteva, Sofiya N., Ross, Brittany N., Gao, Jun, Adikari, Samantha Hiroshini, Zhang, Pengfei, Mourant, Judith R., Wu, Terry H., Werner, James Henry, Torres, Alfredo G., and Hong-Geller, Elizabeth. Increased mortality in mice following immunoprophylaxis therapy with high dosage of nicotinamide in Burkholderia persistent infections. United States: N. p., Web. doi:10.1128/IAI.00592-18.
Micheva-Viteva, Sofiya N., Ross, Brittany N., Gao, Jun, Adikari, Samantha Hiroshini, Zhang, Pengfei, Mourant, Judith R., Wu, Terry H., Werner, James Henry, Torres, Alfredo G., & Hong-Geller, Elizabeth. Increased mortality in mice following immunoprophylaxis therapy with high dosage of nicotinamide in Burkholderia persistent infections. United States. doi:10.1128/IAI.00592-18.
Micheva-Viteva, Sofiya N., Ross, Brittany N., Gao, Jun, Adikari, Samantha Hiroshini, Zhang, Pengfei, Mourant, Judith R., Wu, Terry H., Werner, James Henry, Torres, Alfredo G., and Hong-Geller, Elizabeth. 2018. "Increased mortality in mice following immunoprophylaxis therapy with high dosage of nicotinamide in Burkholderia persistent infections". United States. doi:10.1128/IAI.00592-18. https://www.osti.gov/servlets/purl/1480049.
@article{osti_1480049,
title = {Increased mortality in mice following immunoprophylaxis therapy with high dosage of nicotinamide in Burkholderia persistent infections},
author = {Micheva-Viteva, Sofiya N. and Ross, Brittany N. and Gao, Jun and Adikari, Samantha Hiroshini and Zhang, Pengfei and Mourant, Judith R. and Wu, Terry H. and Werner, James Henry and Torres, Alfredo G. and Hong-Geller, Elizabeth},
abstractNote = {Bacterial persistence, known as non-inherited antibacterial resistance, is a contributing factor to the establishment of long-lasting chronic bacterial infections. In this study, we examined the ability of nicotinamide (NA) to potentiate different classes of antibiotics against Burkholderia thailandensis persister cells. Here we demonstrate that addition of NA in in vitro models of B. thailandensis infection resulted in a significant depletion of the persister population in response to various classes of antibiotics. We applied microfluidic bioreactors with a continuous media flow to study the effect of supplementation with a NA gradient on the recovery of B. thailandensis persister populations. A co-culture of human neutrophils pre-activated with 50 µM NA and B. thailandensis resulted in the most efficient reduction in the persister population. Applying single cell RNA FISH analysis and quantitative PCR, we found that NA inhibited gene expression of the stringent response regulator relA, implicated in the regulation of the persister metabolic state. In conclusion, we also demonstrate that a therapeutic dose of NA (250mg/kg), previously applied as immunoprophylaxis against antibiotic-resistant bacterial species, produced adverse effects in an in vivo murine infection model of the highly pathogenic Burkholderia pseudomallei, indicating that therapeutic dose and metabolite effects have to be carefully evaluated and tailored for every case of potential clinical application.},
doi = {10.1128/IAI.00592-18},
journal = {Infection and Immunity},
number = 1,
volume = 87,
place = {United States},
year = {2018},
month = {10}
}

Works referenced in this record:

Bacterial persistence by RNA endonucleases
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  • Maisonneuve, Etienne; Shakespeare, Lana J.; J�rgensen, Mikkel Girke
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 32, p. 13206-13211
  • DOI: 10.1073/pnas.1100186108

The global, ppGpp-mediated stringent response to amino acid starvation in Escherichia coli
journal, June 2008