Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI82110.15789/2220-7619-2018-4-425-434MOLECULAR BASES OF EPIDEMIOLOGY, DIAGNOSTICS, PREVENTION AND TREATMENT OF INFECTIOUS DISEASESМОЛЕКУЛЯРНЫЕ ОСНОВЫ ЭПИДЕМИОЛОГИИ, ДИАГНОСТИКИ, ПРОФИЛАКТИКИ И ЛЕЧЕНИЯ АКТУАЛЬНЫХ ИНФЕКЦИЙPYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSISУСТОЙЧИВОСТЬ MYCOBACTERIUM TUBERCULOSIS К ПИРАЗИНАМИДУ/ПИРАЗИНОЕВОЙ КИСЛОТЕ: НОВЫЕ СВЕДЕНИЯ И ИХ ЗНАЧЕНИЕ ДЛЯ ПОВЫШЕНИЯ ЭФФЕКТИВНОСТИ ЛЕЧЕНИЯ ТУБЕРКУЛЕЗАAnthonyR. M.ЭнтониР. М.
Netherlands

Richard M. Anthony, Senior Scientist, National Institute for Public Healthand the Environment (RIVM)

P.O. Box 1, 3720 BA Bilthoven, The Netherlands,National Institute for Public Health and the Environment (RIVM).Phone: +31302742363. Fax: +31302744418

старший научный сотрудник

а/я 1, 3720 БА Билтховен, Нидерланды, Национальный институтобщественного здоровья и окружающей среды.Тел.: +31302742363. Факс: +31302744418

richard.anthony@rivm.nlden HertogA. L.Ден ХертогА. Л.
Netherlands

PhD Lecturer, Institute for Life Sciences and Chemistry, HU University of Applied Sciences

преподаватель

National Institute for Public Health and the Environment, BilthovenНациональный институт общественного здоровья и окружающей среды, г. БилтховенInstitute for Life Sciences and Chemistry, HU University of Applied Sciences, UtrechtИнститут медико-биологических наук и химии, Университет прикладных наук, г. Утрехт30122018844254341312201813122018Copyright ©; 2018, Anthony R.M., den Hertog A.L.Copyright ©; 2018, Энтони Р.М., Ден Хертог А.Л.2018Anthony R.M., den Hertog A.L.Энтони Р.М., Ден Хертог А.Л.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/821

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.

Резюме. Пиразинамид (PZA) уникален тем, что является противотуберкулезным препаратом первого ряда как при лечении лекарственно-чувствительного туберкулеза, так и компонентом современных курсов лечения мультирезистентного туберкулеза. Также было показано, что PZA помогает обеспечить длительное лечение и предотвратить рецидив в более коротких схемах приема нескольких лекарств. Пиразинамид является неактивным пролекарством и фермент PncA Mycobacterium tuberculosis превращает его в активную форму — пиразиноевую кислоту (POA). Большинство клинических PZA-резистентных штаммов содержат мутации внутри гена pncA и поэтому остаются восприимчивыми к POA, поскольку не активируют PZA. Устойчивость к активному соединению POA требует альтернативного механизма резистентности, и полученные in vitro POA-резистентные спонтанные мутанты MTB имеют ряд мутаций в гене panD или в серии генов, большинство из которых связаны с регуляцией строгого ответа бактерий. Клинические штаммы MTB, устойчивые к PZA и POA с мутациями в любом из этих генов, являются нетипичными. Таким образом, вероятно, строгий ответ имеет важное значение для MTB в условиях in vivo, а нарушенный ответ приводит к снижению жизнеспособности микроорганизма. Были идентифицированы различные лекарственные соединения-прототипы, нарушающие строгий ответ MTB, которые могут стать основой для препаратов с активностью против латентных форм микобактерий с целью сокращения сроков противотуберкулезного лечения. В данном обзоре мы обсуждаем роль латентного периода в жизненном цикле MTB и возможные связи с активностью PZA с особым вниманием к потенциально новым мишенями и препаратам.

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