Pantothenate and pantetheine antagonize the antitubercular activity of pyrazinamide.

Abstract

Pyrazinamide (PZA) is a first-line tuberculosis drug that inhibits the growth of Mycobacterium tuberculosis via an as yet undefined mechanism. An M. tuberculosis laboratory strain that was auxotrophic for pantothenate was found to be insensitive to PZA and to the active form, pyrazinoic acid (POA). To determine whether this phenotype was strain or condition specific, the effect of pantothenate supplementation on PZA activity was assessed using prototrophic strains of M. tuberculosis. It was found that pantothenate and other β-alanine-containing metabolites abolished PZA and POA susceptibility, suggesting that POA might selectively target pantothenate synthesis. However, when the pantothenate-auxotrophic strain was cultivated using a subantagonistic concentration of pantetheine in lieu of pantothenate, susceptibility to PZA and POA was restored. In addition, we found that β-alanine could not antagonize PZA and POA activity against the pantothenate-auxotrophic strain, indicating that the antagonism is specific to pantothenate. Moreover, pantothenate-mediated antagonism was observed for structurally related compounds, including n-propyl pyrazinoate, 5-chloropyrazinamide, and nicotinamide, but not for nicotinic acid or isoniazid. Taken together, these data demonstrate that while pantothenate can interfere with the action of PZA, pantothenate synthesis is not directly targeted by PZA. Our findings suggest that targeting of pantothenate synthesis has the potential to enhance PZA efficacy and possibly to restore PZA susceptibility in isolates with panD-linked resistance.

• Authors: Nicholas A Dillon, Nicholas D Peterson, Brandon C Rosen, Anthony D Baughn
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 12 Pg. 7258-63 (Dec 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 25246400 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Chemical References

• 5-chloropyrazinamide
• Antitubercular Agents
• beta-Alanine
• Pantothenic Acid
• Niacinamide
• Pyrazinamide
• pyrazinoic acid
• Pantetheine
• propyl pyrazinoate

Topics

• Antitubercular Agents (antagonists & inhibitors, pharmacology)
• Drug Resistance, Bacterial (drug effects)
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects, growth & development, metabolism)
• Niacinamide (metabolism, pharmacology)
• Pantetheine (metabolism, pharmacology)
• Pantothenic Acid (metabolism, pharmacology)
• Pyrazinamide (analogs & derivatives, antagonists & inhibitors, metabolism, pharmacology)
• beta-Alanine (metabolism, pharmacology)