Abstract
Novel antimicrobials for treatment of Mycobacterium tuberculosis are needed. We hypothesized that nicotinamide (NAM) and nicotinic acid (NA) modulate macrophage function to restrict M. tuberculosis 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 restricted growth of bacille Calmette-Guérin but not wild-type Mycobacterium bovis, which both lack a functional nicotinamidase/pyrazinamidase (PncA) rendering each strain resistant to these drugs in broth culture. Interestingly, NAM was not active in macrophages infected with a virulent M. tuberculosis mutant encoding a deletion in pncA. We conclude that the differential activity of NAM and nicotinic acid on infected macrophages suggests host-specific NAM targets rather than PncA-dependent direct antimicrobial properties. These activities are sufficient to restrict attenuated BCG, but not virulent wild-type M. bovis or M. tuberculosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 989-999 |
| Number of pages | 11 |
| Journal | Journal of Infectious Diseases |
| Volume | 221 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 15 2020 |
| Externally published | Yes |
Bibliographical note
Funding Information:Financial support. This work was supported by the Bill & Melinda Gates Foundation (grant OPP1156448 to T. R. H.) and the National Institutes of Health (grants T32AI007044 and K08AI143926 to J. D. S., R01AI093646 to S. J. S., and K24AI137310 to T. R. H.).
Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.
Keywords
- BCG
- Host-directed therapy
- Mycobacterium tuberculosis
- Niacin
- Nicotinamide
- Nicotinic acid
