Multiplex De Novo Sequencing of Peptide Antibiotics

peer-reviewed · Journal of Computational Biology · 2011

peer-reviewed · Journal of Computational Biology · 2011. Hosein Mohimani et al. Proliferation of drug-resistant diseases raises the challenge of searching for new, more efficient…
Date 2011-11-01
Type peer-reviewed
Venue Journal of Computational Biology
Publisher SAGE Publications
Contribution algorithm
DOI 10.1089/cmb.2011.0158
Citations (OpenAlex) 41
Venue 2-year citedness 1.54

Abstract

Proliferation of drug-resistant diseases raises the challenge of searching for new, more efficient antibiotics. Currently, some of the most effective antibiotics (i.e., Vancomycin and Daptomycin) are cyclic peptides produced by non-ribosomal biosynthetic pathways. The isolation and sequencing of cyclic peptide antibiotics, unlike the same activity with linear peptides, is time-consuming and error-prone. The dominant technique for sequencing cyclic peptides is nuclear magnetic resonance (NMR)-based and requires large amounts (milligrams) of purified materials that, for most compounds, are not possible to obtain. Given these facts, there is a need for new tools to sequence cyclic non-ribosomal peptides (NRPs) using picograms of material. Since nearly all cyclic NRPs are produced along with related analogs, we develop a mass spectrometry approach for sequencing all related peptides at once (in contrast to the existing approach that analyzes individual peptides). Our results suggest that instead of attempting to isolate and NMR-sequence the most abundant compound, one should acquire spectra of many related compounds and sequence all of them simultaneously using tandem mass spectrometry. We illustrate applications of this approach by sequencing new variants of cyclic peptide antibiotics from Bacillus brevis, as well as sequencing a previously unknown family of cyclic NRPs produced by marine bacteria. Supplementary Material is available online at www.liebertonline.com/cmb.

Authors

  1. Hosein Mohimani · Carnegie Mellon University, University of California San Diego
  2. Wei-Ting Liu · University of California San Diego
  3. Yu-Liang Yang · University of California San Diego
  4. Susana P. Gaudêncio · Scripps Institution of Oceanography, University of California San Diego
  5. William Fenical · Scripps Institution of Oceanography, University of California San Diego
  6. Pieter C. Dorrestein · Scripps Institution of Oceanography, University of California San Diego, University of California System
  7. Pavel A. Pevzner · Max Planck Institute of Molecular Cell Biology and Genetics, Saint Petersburg Academic University, St Petersburg University, St. Petersburg State University, University of California San Diego, University of Southern California

Methods and tools

  • NRP dereplication and sequencing: Sequences cyclic nonribosomal peptides from multistage mass spectrometry by spectral alignment, and dereplicates them comparatively against known NRPs. The first high-throughput route to a compound class with no genome to search and considerable pharmacological interest.

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