Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria In Vitro and Ex Vivo within Macrophages

Details

Serval ID
serval:BIB_1428E6F17299
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria In Vitro and Ex Vivo within Macrophages
Journal
Antimicrobial Agents and Chemotherapy
Author(s)
Pires , Valente , Simões , Carmo , Testa , Constantino , Anes 
ISSN
0066-4804 (Print)
1098-6596 (Electronic)
ISSN-L
0066-4804
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
59
Number
12
Pages
7693-7699
Language
english
Notes
Publication types: Susceptibility ; research-article Identifiant PubMed Central: PMC4649235
Abstract
Pyrazinamide (PZA) is active against major Mycobacterium tuberculosis species (M. tuberculosis, M. africanum, and M. microti) but not against M. bovis and M. avium. The latter two are mycobacterial species involved in human and cattle tuberculosis and in HIV coinfections, respectively. PZA is a first-line agent for the treatment of human tuberculosis and requires activation by a mycobacterial pyrazinamidase to form the active metabolite pyrazinoic acid (POA). As a result of this mechanism, resistance to PZA, as is often found in tuberculosis patients, is caused by point mutations in pyrazinamidase. In previous work, we have shown that POA esters and amides synthesized in our laboratory were stable in plasma (M. F. Simões, E. Valente, M. J. Gómez, E. Anes, and L. Constantino, Eur J Pharm Sci 37:257-263, 2009, http://dx.doi.org/10.1016/j.ejps.2009.02.012). Although the amides did not present significant activity, the esters were active against sensitive mycobacteria at concentrations 5- to 10-fold lower than those of PZA. Here, we report that these POA derivatives possess antibacterial efficacy in vitro and ex vivo against several species and strains of Mycobacterium with natural or acquired resistance to PZA, including M. bovis and M. avium. Our results indicate that the resistance probably was overcome by cleavage of the prodrugs into POA and a long-chain alcohol. Although it is not possible to rule out that the esters have intrinsic activity per se, we bring evidence here that long-chain fatty alcohols possess a significant antimycobacterial effect against PZA-resistant species and strains and are not mere inactive promoieties. These findings may lead to candidate dual drugs having enhanced activity against both PZA-susceptible and PZA-resistant isolates and being suitable for clinical development.
Keywords
Alcohols/pharmacology, Antitubercular Agents/pharmacology, Cell Survival/drug effects, Macrophages/microbiology, Moraxella (Moraxella) bovis/drug effects, Mycobacterium/drug effects, Mycobacterium avium Complex/drug effects, Mycobacterium tuberculosis/drug effects, Pyrazinamide/analogs & derivatives, Pyrazinamide/chemical synthesis, Pyrazinamide/pharmacology
Pubmed
Web of science
Open Access
Yes
Create date
11/10/2016 16:30
Last modification date
20/08/2019 13:42
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