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 Hiroshini; Zhang, Pengfei; Mourant, Judith R.; Wu, Terry H.; Werner, James Henry; Torres, Alfredo G.; Hong-Geller, Elizabeth

doi:10.1128/IAI.00592-18

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

Journal Article · 15 October 2018 · Infection and Immunity

DOI: https://doi.org/10.1128/IAI.00592-18 · OSTI ID:1480049

^[1]; Ross, Brittany N. ^[2]; Gao, Jun ^[1];

^[1]; Zhang, Pengfei ^[1];

^[1]; Wu, Terry H. ^[3];

^[1]; Torres, Alfredo G. ^[2];

^[1]

Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Univ. of Texas Medical Branch, Galveston, TX (United States)
Univ. of New Mexico Health Sciences Center, Albuquerque, NM (United States)

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.

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Research Organization:: Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: Defense Threat Reduction Agency; USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1480049

Report Number(s):: LA-UR--18-26923

Journal Information:: Infection and Immunity, Journal Name: Infection and Immunity Journal Issue: 1 Vol. 87; ISSN 0019-9567

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: English

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