Antibiotics Sequencing

Peptidic Natural Products (PNPs) and other natural products have an unparalleled track record in pharmacology: most anticancer and antimicrobial agents are natural products or their derivatives. PNPs are divided into two large classes: Non-Ribosomal Peptides (NRPs) and Ribosomally synthesized and Post-translationally modified Peptides (RiPPs). PNPs often contain non-standard amino acids and complex modifications greatly complicating their discovery.

CCMS pioneered the first software for cyclic peptide sequencing and dereplication that was successfully used in many collaborative projects.

Antibiotics Sequencing

Key Publications

Imaging mass spectrometry of intraspecies metabolic exchange revealed the cannibalistic factors of Bacillus subtilis. Liu WT, Yang YL, Xu Y, Lamsa A, Haste NM, Yang JY, Ng J, Gonzalez D, Ellermeier CD, Straight PD, Pevzner PA, Pogliano J, Nizet V, Pogliano K, Dorrestein PC. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16286-90. doi: 10.1073/pnas.1008368107. Epub 2010 Aug 30.
Sequencing cyclic peptides by multistage mass spectrometry. Mohimani H, Yang YL, Liu WT, Hsieh PW, Dorrestein PC, Pevzner PA. Proteomics. 2011 Sep;11(18):3642-50. doi: 10.1002/pmic.201000697. Epub 2011 Aug 9.
Cycloquest: identification of cyclopeptides via database search of their mass spectra against genome databases. Mohimani H, Liu WT, Mylne JS, Poth AG, Colgrave ML, Tran D, Selsted ME, Dorrestein PC, Pevzner PA. J Proteome Res. 2011 Oct 7;10(10):4505-12. doi: 10.1021/pr200323a. Epub 2011 Sep 7.
Multiplex de novo sequencing of peptide antibiotics. Mohimani H, Liu WT, Yang YL, Gaudêncio SP, Fenical W, Dorrestein PC, Pevzner PA. J Comput Biol. 2011 Nov;18(11):1371-81. doi: 10.1089/cmb.2011.0158. Epub 2011 Oct 28.
Sequencing-grade de novo analysis of MS/MS triplets (CID/HCD/ETD) from overlapping peptides. Guthals A, Clauser KR, Frank AM, Bandeira N. J Proteome Res. 2013 Jun 7;12(6):2846-57.
A New Approach to Evaluating Statistical Significance of Spectral Identifications. Mohimani H, Kim S, Pevzner PA. J Proteome Res. 2013 Apr 5;12(4):1560-8. doi: 10.1021/pr300453t. Epub 2013 Mar 8.
View All CCMS Publictions

Jointly with leading PNP researchers Drs. Dorrestein, Fenical, Gerwick, and Moore, CCMS developed the first software for cyclic peptide sequencing, identification, and dereplication that was successfully used in nearly two dozens of collaborative projects. However, despite this initial success, our software has not capitalized yet on recent progress in genome sequencing. In particular, while PNP-producing bacteria are often difficult to cultivate, computational advances in single cell genomics in the last year removed this requirement by sequencing genomes from single cells. Thus, future MS-based PNP sequencing projects should start from genome sequencing (if the genome of a PNP-producing organism is not available), followed by prediction of all PNP byosynthetic gene clusters and all putative PNPs produced by these clusters. In the case of NRPs, such predictions should be made using the non-ribosomal genetic code often resulting in ambiguities and multiple peptides.

CCMS is integrating MS and genomics for matching putative PNPs (predicted using analysis of biosynthetic gene clusters coding for PNPs) against MS data. In collaboration with Pieter Dorrestein and Bradley Moore, CCMS recently identified informatipeptine, the first PNP discovered in a fully automated fashion. We anticipate that this approach will result in dozens of PNPs identified from a bacterial community in a single MS experiment. Efficient sequencing of PNPs, if successful, will represent a disruptive computational technology for antibiotics discovery and human microbiome analysis.