文章基本信息

标题：Multiplexed transcriptional repression identifies a network of bactericidal interactions between mycobacterial respiratory complexes
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作者：Matthew B. McNeil ; Heath W. Ryburn ; Justin Tirados 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：1
页码：1-16
DOI：10.1016/j.isci.2021.103573
语种：English
出版社：Elsevier
摘要：SummaryMycobacterium tuberculosisremains a leading cause of infectious disease morbidity and mortality for which new drug combination therapies are needed. Combinations of respiratory inhibitors can have synergistic or synthetic lethal interactions with sterilizing activity, suggesting that regimens with multiple bioenergetic inhibitors could shorten treatment times. However, realizing this potential requires an understanding of which combinations of respiratory complexes, when inhibited, have the strongest consequences on bacterial growth and viability. Here we have used multiplex CRISPR interference (CRISPRi) andMycobacterium smegmatisas a physiological and molecular model for mycobacterial respiration to identify interactions between respiratory complexes. In this study, we identified synthetic lethal and synergistic interactions between respiratory complexes and demonstrated how the engineering of CRISPRi-guide sequences can be used to further explore networks of interacting gene pairs. These results provide fundamental insights into the functions of and interactions between bioenergetic complexes and the utility of CRISPRi in designing drug combinations.Graphical abstractDisplay OmittedHighlights•We identified interactions between respiratory complexes using multiplexed CRISPRi•CRISPRi sgRNAs with reduced efficacy expanded the network of interacting complexes•Strength of lethal interactions is influenced by gene pair and metabolic stateTropical medicine; Drugs; Microbiology