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.
Highlights
Mycobacterium tuberculosis is estimated to infect 23%–32% of the world [1, 2] and is the leading infectious killer [3]
Considering some treatment success with NAM in humans and the accumulating evidence that Nicotinic acid (NA) and NAM can modulate macrophage function, we hypothesized that these PZA analogues limit M. tuberculosis replication through hostspecific targets, in addition to their known antimycobacterial properties. We confirmed that both compounds had modest direct antimicrobial activity limiting M. tuberculosis growth in broth culture at neutral pH, but only NAM was active within the macrophage. These results suggest a host-specific activity of NAM, which was further supported by experiments using Mycobacterium bovis bacille Calmette-Guérin (BCG), which is resistant to NAM and PZA due to a nonfunctional nicotinamidase/pyrazinamidase (PncA) required for activation of both of these prodrugs
We found that both NA and NAM have modest direct antimicrobial activity in broth culture, whereas only NAM restricts M. tuberculosis growth within monocyte-derived macrophages (MDMs) and alveolar macrophages
Summary
Mycobacterium tuberculosis is estimated to infect 23%–32% of the world [1, 2] and is the leading infectious killer [3]. Antagonism of INH activity by NAM is poorly defined, but it may be mechanistically similar to the well-described PZAmediated INH antagonism, considering the structural similarity of these derivatives [13, 14] Despite this antagonism, PZA remains essential to early sterilizing activity and shortens the required duration of therapy from >9 months to 6 months [15]. NAM and NA are known to have pleiotropic activities on host inflammatory and metabolic pathways These drugs are largely associated with anti-inflammatory effects, including down-regulation of proinflammatory cytokine secretion [20,21,22,23], disruption of M1 macrophage differentiation
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