Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides.

Olga Kunyavskaya,Hosein Mohimani,Pieter C Dorrestein,Azat M Tagirdzhanov,Louis-Félix Nothias,Andrés Mauricio Caraballo-Rodríguez,Anton Korobeynikov,Alexey Gurevich

doi:10.3390/metabo11100693

Abstract

Microbial natural products are a major source of bioactive compounds for drug discovery. Among these molecules, nonribosomal peptides (NRPs) represent a diverse class of natural products that include antibiotics, immunosuppressants, and anticancer agents. Recent breakthroughs in natural product discovery have revealed the chemical structure of several thousand NRPs. However, biosynthetic gene clusters (BGCs) encoding them are known only for a few hundred compounds. Here, we developed Nerpa, a computational method for the high-throughput discovery of novel BGCs responsible for producing known NRPs. After searching 13,399 representative bacterial genomes from the RefSeq repository against 8368 known NRPs, Nerpa linked 117 BGCs to their products. We further experimentally validated the predicted BGC of ngercheumicin from Photobacterium galatheae via mass spectrometry. Nerpa supports searching new genomes against thousands of known NRP structures, and novel molecular structures against tens of thousands of bacterial genomes. The availability of these tools can enhance our understanding of NRP synthesis and the function of their biosynthetic enzymes.

Highlights

Nerpa takes as input an nonribosomal peptides (NRPs) database and nucleotide sequences including complete genomes and draft assemblies (Figure 1)
In (i) and (ii), Nerpa relies on the leading third-party NRP retro-biosynthesis and genome mining software, namely rBAN [33] and antiSMASH v5 [16], integrated with the pipeline
Since the PNPdatabase and NP Atlas metadata lacks the classification into NRPs and non-NRPs, some compounds represent other classes of peptidic natural products such as ribosomally synthesized and post-translationally modified peptides (RiPPs). We partially addressed this problem by excluding from pNRPdb all compounds identical to known RiPPs from MIBiG and RiPPDB [36] along with their stereoisomers

Summary

Introduction

Nonribosomal peptides (NRPs) are promising natural sources of antibiotics, immunosuppressants, anticancer agents, toxins, siderophores, pigments, and cytostatics [1]. Starting from penicillin [2], researchers revealed the chemical structure of several thousand. The mechanism of their biosynthesis remained unclear until the end of the 20th century [4,5]. Only 10% of known NRPs are associated with genes encoding them [6]

Methods

Results

Conclusion