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

• Published in: Infection and immunity 2019-01, Vol.87 (1)
• Main Authors: Micheva-Viteva, Sofiya N, Ross, Brittany N, Gao, Jun, Adikari, Samantha, Zhang, Pengfei, Mourant, Judith R, Wu, Terry H, Werner, James H, Torres, Alfredo G, Hong-Geller, Elizabeth
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Bacterial Infections; Burkholderia Infections - drug therapy; Disease Models, Animal; Female; Mice, Inbred BALB C; Niacinamide - administration & dosage; Niacinamide - adverse effects; Survival Analysis; Vitamin B Complex - administration & dosage; Vitamin B Complex - adverse effects
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00592-18

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 persister cells. Here we demonstrate that addition of NA in models of 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 persister populations. A coculture of human neutrophils preactivated with 50 µM NA and resulted in the most efficient reduction in the persister population. Applying single-cell RNA fluorescence hybridization analysis and quantitative PCR, we found that NA inhibited gene expression of the stringent response regulator , 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 murine model of infection with the highly pathogenic bacterium , indicating that therapeutic dose and metabolite effects have to be carefully evaluated and tailored for every case of potential clinical application.