Chemical genomics informs antibiotic and essential gene function in Acinetobacter baumannii

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.

• Publication year

  2025

• Venue

  PLoS Genetics

• Publication date

  2025-03-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1371/journal.pgen.1011642PMID 40153700PMCID 11975115
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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