PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS

Abstract. Pyrazinamide (PZA) is unique in that it is a component of the first line therapy for drug sensitive tuberculosis and in most current and experimental treatments also for multi drug resistant tuberculosis. Furthermore, PZA has been shown to help to ensure lasting cure and prevent relapse in...

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Autores principales:	R. M. Anthony, A. L. den Hertog
Formato:	article
Lenguaje:	RU
Publicado:	Sankt-Peterburg : NIIÈM imeni Pastera 2018
Materias:	mycobacterium tuberculosis drug resistance pyrazinamide pyrazinoic acid latent tuberculosis Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/f1887f2eca534864a7aa89f5d09b7057
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spelling	oai:doaj.org-article:f1887f2eca534864a7aa89f5d09b70572021-11-22T07:09:49ZPYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS2220-76192313-739810.15789/2220-7619-2018-4-425-434https://doaj.org/article/f1887f2eca534864a7aa89f5d09b70572018-12-01T00:00:00Zhttps://www.iimmun.ru/iimm/article/view/821https://doaj.org/toc/2220-7619https://doaj.org/toc/2313-7398Abstract. Pyrazinamide (PZA) is unique in that it is a component of the first line therapy for drug sensitive tuberculosis and in most current and experimental treatments also for multi drug resistant tuberculosis. Furthermore, PZA has been shown to help to ensure lasting cure and prevent relapse in shorter multi drug regimens. PZA is a prodrug. Mycobacterial tuberculosis (MTB) PncA enzyme activates the anti-mycobacterial prodrug PZA by transforming it into pyrazinoic acid (POA). The majority of clinical PZA resistant isolates contain mutations within the pncA gene and therefore remain sensitive to POA as they no longer activate PZA. Resistance to the active compound POA requires an alternative resistance mechanism and in vitro selected spontaneous MTB POA resistant mutants typically acquire a range of mutations in panD or mutations in one of a series of genes most of which are associated with the regulation of the bacterial stringent response. Clinically isolated PZA resistant MTB strains resistant to PZA and POA with mutations in any of these genes are unusual. Thus, it is likely the stringent response is critical for MTB in vivo and a damaged stringent response results in at least a reduction in fitness. Various lead compounds that disrupt the MTB stringent response have been identified that might form the basis for drugs with activity against latent mycobacteria with the potential to shorten tuberculosis treatment. Here we discuss the role of latency in the lifecycle of MTB and possible links to the activity PZA with a focus on potential new targets and drugs.R. M. AnthonyA. L. den HertogSankt-Peterburg : NIIÈM imeni Pasteraarticlemycobacterium tuberculosisdrug resistancepyrazinamidepyrazinoic acidlatent tuberculosisInfectious and parasitic diseasesRC109-216RUInfekciâ i Immunitet, Vol 8, Iss 4, Pp 425-434 (2018)
institution	DOAJ
collection	DOAJ
language	RU
topic	mycobacterium tuberculosis drug resistance pyrazinamide pyrazinoic acid latent tuberculosis Infectious and parasitic diseases RC109-216
spellingShingle	mycobacterium tuberculosis drug resistance pyrazinamide pyrazinoic acid latent tuberculosis Infectious and parasitic diseases RC109-216 R. M. Anthony A. L. den Hertog PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS
description	Abstract. Pyrazinamide (PZA) is unique in that it is a component of the first line therapy for drug sensitive tuberculosis and in most current and experimental treatments also for multi drug resistant tuberculosis. Furthermore, PZA has been shown to help to ensure lasting cure and prevent relapse in shorter multi drug regimens. PZA is a prodrug. Mycobacterial tuberculosis (MTB) PncA enzyme activates the anti-mycobacterial prodrug PZA by transforming it into pyrazinoic acid (POA). The majority of clinical PZA resistant isolates contain mutations within the pncA gene and therefore remain sensitive to POA as they no longer activate PZA. Resistance to the active compound POA requires an alternative resistance mechanism and in vitro selected spontaneous MTB POA resistant mutants typically acquire a range of mutations in panD or mutations in one of a series of genes most of which are associated with the regulation of the bacterial stringent response. Clinically isolated PZA resistant MTB strains resistant to PZA and POA with mutations in any of these genes are unusual. Thus, it is likely the stringent response is critical for MTB in vivo and a damaged stringent response results in at least a reduction in fitness. Various lead compounds that disrupt the MTB stringent response have been identified that might form the basis for drugs with activity against latent mycobacteria with the potential to shorten tuberculosis treatment. Here we discuss the role of latency in the lifecycle of MTB and possible links to the activity PZA with a focus on potential new targets and drugs.
format	article
author	R. M. Anthony A. L. den Hertog
author_facet	R. M. Anthony A. L. den Hertog
author_sort	R. M. Anthony
title	PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS
title_short	PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS
title_full	PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS
title_fullStr	PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS
title_full_unstemmed	PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS
title_sort	pyrazinamide/pyrazinoic acid resistance in mycobacterium tuberculosis: recent findings and implications for improving the treatment of tuberculosis
publisher	Sankt-Peterburg : NIIÈM imeni Pastera
publishDate	2018
url	https://doaj.org/article/f1887f2eca534864a7aa89f5d09b7057
work_keys_str_mv	AT rmanthony pyrazinamidepyrazinoicacidresistanceinmycobacteriumtuberculosisrecentfindingsandimplicationsforimprovingthetreatmentoftuberculosis AT aldenhertog pyrazinamidepyrazinoicacidresistanceinmycobacteriumtuberculosisrecentfindingsandimplicationsforimprovingthetreatmentoftuberculosis
_version_	1718418015050006528

PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS

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