Стратегия создания новых антимикотиков, действующих на клеточную стенку и клеточную мембрану грибов

Актуальность. Инвазивные микозы представляют растущую угрозу для здоровья, особенно для пациентов с ослабленным иммунитетом, количество которых увеличивается благодаря прогрессу в онкологии, трансплантологии и реаниматологии. Применение существующих антимикотиков ограничено их токсичностью, узким спектром действия, низкой биодоступностью и растущей резистентностью патогенов. Медленные темпы разработки новых антимикотиков по сравнению с антибактериальными препаратами усугубляют ситуацию, что делает поиск новых эффективных и безопасных препаратов чрезвычайно актуальным. Цель обзора — обобщить и систематизировать сведения о современных направлениях в разработке антимикотиков, охватывающие эволюцию подходов к «классическим» мишеням (клеточная стенка, клеточная мембрана) и стратегии, нацеленные на преодоление текущих ограничений противогрибковой терапии. Методы. Систематический анализ научной литературы и данных клинических исследований с использованием баз данных Google Scholar, eLibrary, PubMed, Wally и ClinicalTrials.gov. Основное внимание уделено публикациям последнего десятилетия и ключевым работам более раннего периода. Результаты. За последние 10 лет в клиническую практику вошли лишь 4 новых препарата. В стадии активных клинических исследований находятся 9 молекул, включая ингибиторы Gwt1, дигидро-оротатдегидрогеназы и ингаляционные триазолы. Перспективны соединения с новыми механизмами действия, например, мандимицин, нацеленный на фосфолипиды, ингибиторы отсутствующей у человека синтазы инозитол-фосфоцерамида. Заключение. Несмотря на вызовы, связанные с эукариотической природой грибов, разработка новых антимикотиков продолжается по нескольким перспективным направлениям, заключающимся в улучшении свойств представителей существующих классов и поиском принципиально новых мишеней.

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