Genome-wide mutant profiling predicts the mechanism of a Lipid II binding antibiotic article

Marina Santiago, Wonsik Lee, Antoine Abou Fayad, Kathryn A. Coe, Mithila Rajagopal, Truc Do, Fabienne Hennessen, Veerasak Srisuknimit, Rolf Müller, Timothy C. Meredith, Suzanne Walker

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Identifying targets of antibacterial compounds remains a challenging step in the development of antibiotics. We have developed a two-pronged functional genomics approach to predict mechanism of action that uses mutant fitness data from antibiotic-treated transposon libraries containing both upregulation and inactivation mutants. We treated a Staphylococcus aureus transposon library containing 690,000 unique insertions with 32 antibiotics. Upregulation signatures identified from directional biases in insertions revealed known molecular targets and resistance mechanisms for the majority of these. Because single-gene upregulation does not always confer resistance, we used a complementary machine-learning approach to predict the mechanism from inactivation mutant fitness profiles. This approach suggested the cell wall precursor Lipid II as the molecular target of the lysocins, a mechanism we have confirmed. We conclude that docking to membrane-anchored Lipid II precedes the selective bacteriolysis that distinguishes these lytic natural products, showing the utility of our approach for nominating the antibiotic mechanism of action.

Original languageEnglish (US)
Pages (from-to)601-608
Number of pages8
JournalNature Chemical Biology
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2018

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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