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. 2011 Nov 16;133(45):18010-3.
doi: 10.1021/ja2040877. Epub 2011 Oct 24.

Imaging mass spectrometry and genome mining via short sequence tagging identified the anti-infective agent arylomycin in Streptomyces roseosporus

Wei-Ting Liu  1 , Roland D Kersten, Yu-Liang Yang, Bradley S Moore, Pieter C Dorrestein
Affiliations

Imaging mass spectrometry and genome mining via short sequence tagging identified the anti-infective agent arylomycin in Streptomyces roseosporus

Wei-Ting Liu et al. J Am Chem Soc. .

Abstract

Here, we described the discovery of anti-infective agent arylomycin and its biosynthetic gene cluster in an industrial daptomycin producing strain Streptomyces roseosporus. This was accomplished via the use of MALDI imaging mass spectrometry (IMS) along with peptidogenomic approach in which we have expanded to short sequence tagging (SST) described herein. Using IMS, we observed that prior to the production of daptomycin, a cluster of ions (1-3) was produced by S. roseosporus and correlated well with the decreased staphylococcal cell growth. With a further adopted SST peptidogenomics approach, which relies on the generation of sequence tags from tandem mass spectrometric data and query against genomes to identify the biosynthetic genes, we were able to identify these three molecules (1-3) to arylomycins, a class of broad-spectrum antibiotics that target type I signal peptidase. The gene cluster was then identified. This highlights the strength of IMS and MS guided genome mining approaches in effectively bridging the gap between phenotypes, chemotypes, and genotypes.

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Figures

Figure 1
Figure 1. Structures of NRPS-derived compounds
Arylomycins and daptomycin have various components with different fatty acid (FA) (labeled in blue) chain lengths. Bis-aryl bridges are highlighted in red.
Figure 2
Figure 2. IMS of S. roseosporus spotted on top of a S. epidermidis lawn
(1) ion distribution of compound 1–3 (863, 877, 891) observed in IMS. 1i is a photograph showing S. roseosporus inhibit Staphylococci growth. (2) Superimposition of the photograph with IMS data on top of MALDI target plate. Average mass spectrum of each IMS experiment was shown below IMS images with signals correlated to compound 1–3 labeled with corresponding color as displayed in images.
Figure 3
Figure 3. Correlate compound 1–3 to arylomycins
(A) Alignment of IT MS/MS of compounds 1–3 revealed sequence tag Gly-Ala. (B) Annotated ion table corresponds to the IT MS/MS of compound 1. (C) Ion map showing the fragmentation pattern of compound 1 correlates to arylomycin A2.
Scheme 1
Scheme 1. Arylomycin biosynthetic gene cluster and proposed biosynthetic pathway
See this image and copyright information in PMC

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