The Natural Product Elegaphenone Potentiates Antibiotic Effects against Pseudomonas aeruginosa

• Type of Material: Article
• Authors: Weining Zhao, Technical University of Munich; Ashley R. Cross, Emory University; Caillan Crowe-McAuliffe, University of Hamburg; Angela Weigert-Munoz, Technical University of Munich; Erika E. Csatary, Emory University; Amy E. Solinski, Emory University; Joanna Krysiak, Technical University of Munich; Joanna Goldberg, Emory University; Daniel N. Wilson, University of Hamburg; Eva Medina, Helmholtz Centre for Infection Research; William Wuest, Emory University; Stephan A. Sieber, Technical University of Munich
• Language: English
• Date: 2019-06-17
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 John Wiley & Sons, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1002/anie.201903472
• Title of Journal or Parent Work: Angewandte Chemie: International Edition
• Volume: 58
• Issue: 25
• Start Page: 8581
• End Page: 8584
• Grant/Funding Information: By the National Science Foundation CHE1755698 (W.M.W.) and the National Institute of General Medical Sciences GM119426 (W.M.W.).; A.R.C. was supported in part by the CF@LANTA RDP Fellowship Program from the Cystic Fibrosis Foundation (MCCART15R0).; The work was funded by grants of the Deutsche Forschungsgemeinschaft (SI-1096/10–1 to S.A.S. and WI3285/6–1 to D.N.W.)
• Keywords: Chemistry; natural products; Pyocyanin; Probes; ALGP; Chemistry, Multidisciplinary; antibiotics; Physical Sciences; Mucoidy; Sequence; Science & Technology; Transposon mutant library; Pseudomonas aeruginosa; chemical proteomics; virulence
• Research Categories: Chemistry, Pharmaceutical; Biology, Microbiology; Health Sciences, Immunology; Chemistry, Biochemistry

Abstract

Natural products represent a rich source of antibiotics that address versatile cellular targets. The deconvolution of their targets via chemical proteomics is often challenged by the introduction of large photocrosslinkers. Here we applied elegaphenone, a largely uncharacterized natural product antibiotic bearing a native benzophenone core scaffold, for affinity-based protein profiling (AfBPP) in Gram-positive and Gram-negative bacteria. This study utilizes the alkynylated natural product scaffold as a probe to uncover intriguing biological interactions with the transcriptional regulator AlgP. Furthermore, proteome profiling of a Pseudomonas aeruginosa AlgP transposon mutant provided unique insights into the mode of action. Elegaphenone enhanced the elimination of intracellular P. aeruginosa in macrophages exposed to sub-inhibitory concentrations of the fluoroquinolone antibiotic norfloxacin.