Cell chemical biology · 2023
Antiplasmodial peptaibols act through membrane directed mechanisms.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Collins Jennifer E, Lee Jin Woo, Rocamora Frances, Saggu Gagandeep S, Wendt Karen L, Pasaje Charisse Flerida A, Smick Sebastian, Santos Natalia Mojica, Paes Raphaella, Jiang Tiantian, Mittal Nimisha, Luth Madeline R, Chin Taylor, Chang Howard, McLellan James L, Morales-Hernandez Beatriz, Hanson Kirsten K, Niles Jacquin C, Desai Sanjay A, Winzeler Elizabeth A, Cichewicz Robert H, Chakrabarti Debopam
Аннотация
Our previous study identified 52 antiplasmodial peptaibols isolated from fungi. To understand their antiplasmodial mechanism of action, we conducted phenotypic assays, assessed the in vitro evolution of resistance, and performed a transcriptome analysis of the most potent peptaibol, HZ NPDG-I. HZ NPDG-I and 2 additional peptaibols were compared for their killing action and stage dependency, each showing a loss of digestive vacuole (DV) content via ultrastructural analysis. HZ NPDG-I demonstrated a stepwise increase in DV pH, impaired DV membrane permeability, and the ability to form ion channels upon reconstitution in planar membranes. This compound showed no signs of cross resistance to targets of current clinical candidates, and 3 independent lines evolved to resist HZ NPDG-I acquired nonsynonymous changes in the P. falciparum multidrug resistance transporter, pfmdr1. Conditional knockdown of PfMDR1 showed varying effects to other peptaibol analogs, suggesting differing sensitivity.