Chemical genomics informs antibiotic and essential gene function in Acinetobacter baumannii.

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
PLoS Genetics Pub Date : 2025-03-28 eCollection Date: 2025-03-01 DOI:10.1371/journal.pgen.1011642
Jennifer Suzanne Tran, Ryan David Ward, Rubén Iruegas-López, Ingo Ebersberger, Jason Matthew Peters
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引用次数: 0

Abstract

The Gram-negative pathogen, Acinetobacter baumannii, poses a serious threat to human health due to its role in nosocomial infections that are resistant to treatment with current antibiotics. Despite this, our understanding of fundamental A. baumannii biology remains limited, as many essential genes have not been experimentally characterized. These essential genes are critical for bacterial survival and, thus, represent promising targets for drug discovery. Here, we systematically probe the function of essential genes by screening a CRISPR interference knockdown library against a diverse panel of chemical inhibitors, including antibiotics. We find that most essential genes show chemical-gene interactions, allowing insights into both inhibitor and gene function. For instance, knockdown of lipooligosaccharide (LOS) transport genes increased sensitivity to a broad range of chemicals. Cells with defective LOS transport showed cell envelope hyper-permeability that was dependent on continued LOS synthesis. Using phenotypes across our chemical-gene interaction dataset, we constructed an essential gene network linking poorly understood genes to well-characterized genes in cell division and other processes. Finally, our phenotype-structure analysis identified structurally related antibiotics with distinct cellular impacts and suggested potential targets for underexplored inhibitors. This study advances our understanding of essential gene and inhibitor function, providing a valuable resource for mechanistic studies, therapeutic strategies, and future key targets for antibiotic development.

化学基因组学揭示了鲍曼不动杆菌的抗生素和必需基因功能。
革兰氏阴性病原体鲍曼不动杆菌对人类健康构成严重威胁,因为它在医院感染中起作用,对目前的抗生素治疗具有耐药性。尽管如此,我们对鲍曼不动杆菌基本生物学的了解仍然有限,因为许多必需基因尚未通过实验表征。这些必需基因对细菌的生存至关重要,因此是药物发现的有希望的靶点。在这里,我们通过筛选CRISPR干扰敲低文库来系统地探测必需基因的功能,以对抗多种化学抑制剂,包括抗生素。我们发现大多数基本基因显示化学-基因相互作用,允许深入了解抑制剂和基因功能。例如,低脂低聚糖(LOS)转运基因的敲低增加了对多种化学物质的敏感性。LOS运输缺陷的细胞表现出依赖于LOS持续合成的包膜超通透性。利用化学-基因相互作用数据集的表型,我们构建了一个基本的基因网络,将细胞分裂和其他过程中鲜为人知的基因与特征良好的基因联系起来。最后,我们的表型结构分析确定了具有不同细胞影响的结构相关抗生素,并提出了未开发抑制剂的潜在靶点。这项研究促进了我们对关键基因和抑制剂功能的理解,为机制研究、治疗策略和未来抗生素开发的关键靶点提供了宝贵的资源。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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