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J Infect Dis. 2019 Oct 31. pii: jiz541. doi: 10.1093/infdis/jiz541. [Epub ahead of print]

Nicotinamide limits replication of Mycobacterium tuberculosis and BCG within macrophages.

Author information

1
TB Research & Training Center, Department of Medicine, University of Washington, Seattle, WA, USA.
2
Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA.
3
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
4
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
5
Department of Microbiology, University of Washington, Seattle, WA, USA.

Abstract

Novel antimicrobials for treatment of Mycobacterium tuberculosis (Mtb) are needed. We hypothesized that nicotinamide (NAM) and nicotinic acid (NA) modulate macrophage function to restrict Mtb replication in addition to their direct antimicrobial properties. Both compounds had modest activity in 7H9 broth, but only NAM inhibited replication in macrophages. Surprisingly, in macrophages NAM and the related compound pyrazinamide (PZA) restricted growth of BCG but not wild-type M.bovis, which both lack a functional PncA amidase rendering each strain resistant to these drugs in broth culture. Interestingly, NAM was not active in macrophages infected with a virulent Mtb mutant encoding a deletion in pncA. We conclude that the differential activity of NAM and NA on infected macrophages suggests host-specific NAM targets that are associated with M. bovis strain virulence rather than PncA-dependent direct antimicrobial properties. These activities are sufficient to restrict attenuated BCG, but not virulent wild-type M. bovis or Mtb.

KEYWORDS:

Mycobacterium tuberculosis ; BCG; Nicotinamide; host-directed therapy; niacin; nicotinic acid

PMID:
31665359
DOI:
10.1093/infdis/jiz541

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