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.

Handle URI:
http://hdl.handle.net/10754/579544
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.
Authors:
Pires, David; Valente, Emília; Simoes, Marta; Carmo, Nuno; Testa, Bernard; Constantino, Luís; Anes, Elsa
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 mycobacteria species involved in human and cattle tuberculosis and in HIV co-infections, 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 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. 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 was probably overcome by cleavage of the prodrugs into POA and a long-chain alcohol. Although it is not possible to rule out that the esters may have intrinsic activity per se, we bring evidence here that long-chain fatty alcohols possess a significant anti-mycobacterial 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.
KAUST Department:
Computational Bioscience Research Center (CBRC); Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Citation:
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. 2015:AAC.00936-15 Antimicrobial Agents and Chemotherapy
Publisher:
American Society for Microbiology
Journal:
Antimicrobial Agents and Chemotherapy
Issue Date:
5-Oct-2015
DOI:
10.1128/AAC.00936-15
Type:
Article
ISSN:
0066-4804; 1098-6596
Additional Links:
http://aac.asm.org/lookup/doi/10.1128/AAC.00936-15
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC); Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorPires, Daviden
dc.contributor.authorValente, Emíliaen
dc.contributor.authorSimoes, Martaen
dc.contributor.authorCarmo, Nunoen
dc.contributor.authorTesta, Bernarden
dc.contributor.authorConstantino, Luísen
dc.contributor.authorAnes, Elsaen
dc.date.accessioned2015-10-11T11:11:20Zen
dc.date.available2015-10-11T11:11:20Zen
dc.date.issued2015-10-05en
dc.identifier.citationEsters of pyrazinoic acid are active against pyrazinamide-resistant strains of Mycobacterium tuberculosis and other naturally resistant mycobacteria in vitro and ex vivo within macrophages. 2015:AAC.00936-15 Antimicrobial Agents and Chemotherapyen
dc.identifier.issn0066-4804en
dc.identifier.issn1098-6596en
dc.identifier.doi10.1128/AAC.00936-15en
dc.identifier.urihttp://hdl.handle.net/10754/579544en
dc.description.abstractPyrazinamide (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 mycobacteria species involved in human and cattle tuberculosis and in HIV co-infections, 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 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. 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 was probably overcome by cleavage of the prodrugs into POA and a long-chain alcohol. Although it is not possible to rule out that the esters may have intrinsic activity per se, we bring evidence here that long-chain fatty alcohols possess a significant anti-mycobacterial 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.en
dc.language.isoenen
dc.publisherAmerican Society for Microbiologyen
dc.relation.urlhttp://aac.asm.org/lookup/doi/10.1128/AAC.00936-15en
dc.rightsArchived with thanks to Antimicrobial Agents and Chemotherapyen
dc.titleEsters of pyrazinoic acid are active against pyrazinamide-resistant strains of Mycobacterium tuberculosis and other naturally resistant mycobacteria in vitro and ex vivo within macrophages.en
dc.typeArticleen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Divisionen
dc.identifier.journalAntimicrobial Agents and Chemotherapyen
dc.eprint.versionPost-printen
dc.contributor.institutionResearch Institute for Medicines, iMed-ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Portugal.en
dc.contributor.institutionInstituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.en
dc.contributor.institutionDepartment of Pharmacy, Lausanne University Hospital (CHUV), Lausanne, Switzerland.en
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorSimoes, Martaen
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