Increased Mortality in Mice following Immunoprophylaxis Therapy with High Dosage of Nicotinamide in Burkholderia Persistent Infections

Sofiya N. Micheva-Viteva, Brittany N. Ross, Jun Gao, Samantha Adikari, Pengfei Zhang, Judith R. Mourant, Terry H. Wu, James H. Werner, Alfredo Torres, Elizabeth Hong-Geller

Research output: Contribution to journalArticle

Abstract

Bacterial persistence, known as noninherited antibacterial resistance, is a factor contributing to the establishment of long-lasting chronic bacterial infections. In this study, we examined the ability of nicotinamide (NA) to potentiate the activity of 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 medium flow to study the effect of supplementation with an NA gradient on the recovery of B. thailandensis persister populations. A coculture of human neutrophils preactivated with 50 µM NA and B. thailandensis resulted in the most efficient reduction in the persister population. Applying single-cell RNA fluorescence in situ hybridization 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. We also demonstrate that a therapeutic dose of NA (250 mg/kg of body weight), previously applied as immunoprophylaxis against antibiotic-resistant bacterial species, produced adverse effects in an in vivo murine model of infection with the highly pathogenic bacterium Burkholderia pseudomallei, indicating that therapeutic dose and metabolite effects have to be carefully evaluated and tailored for every case of potential clinical application.

Original languageEnglish (US)
JournalInfection and Immunity
Volume87
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Burkholderia Infections
Niacinamide
Mortality
Anti-Bacterial Agents
Therapeutics
Burkholderia pseudomallei
Burkholderia
Population
Microfluidics
Bioreactors
Coculture Techniques
Infection
Fluorescence In Situ Hybridization
Bacterial Infections
Neutrophils
Body Weight
RNA
Bacteria
Gene Expression
Polymerase Chain Reaction

Keywords

  • antimicrobial resistance
  • bacterial persistence
  • Burkholderia
  • microfluidics
  • nicotinamide
  • relA

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Increased Mortality in Mice following Immunoprophylaxis Therapy with High Dosage of Nicotinamide in Burkholderia Persistent Infections. / Micheva-Viteva, Sofiya N.; Ross, Brittany N.; Gao, Jun; Adikari, Samantha; Zhang, Pengfei; Mourant, Judith R.; Wu, Terry H.; Werner, James H.; Torres, Alfredo; Hong-Geller, Elizabeth.

In: Infection and Immunity, Vol. 87, No. 1, 01.01.2019.

Research output: Contribution to journalArticle

Micheva-Viteva, SN, Ross, BN, Gao, J, Adikari, S, Zhang, P, Mourant, JR, Wu, TH, Werner, JH, Torres, A & Hong-Geller, E 2019, 'Increased Mortality in Mice following Immunoprophylaxis Therapy with High Dosage of Nicotinamide in Burkholderia Persistent Infections' Infection and Immunity, vol. 87, no. 1. https://doi.org/10.1128/IAI.00592-18
Micheva-Viteva, Sofiya N. ; Ross, Brittany N. ; Gao, Jun ; Adikari, Samantha ; Zhang, Pengfei ; Mourant, Judith R. ; Wu, Terry H. ; Werner, James H. ; Torres, Alfredo ; Hong-Geller, Elizabeth. / Increased Mortality in Mice following Immunoprophylaxis Therapy with High Dosage of Nicotinamide in Burkholderia Persistent Infections. In: Infection and Immunity. 2019 ; Vol. 87, No. 1.
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