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Metagenome‐Guided Analogue Synthesis Yields Improved Gram‐Negative‐Active Albicidin‐ and Cystobactamid‐Type Antibiotics
Author(s) -
Wang Zongqiang,
Kasper Amanda,
Mehmood Rabia,
Ternei Melinda,
Li Shaogang,
Freundlich Joel S.,
Brady Sean F.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202104874
Subject(s) - metagenomics , antibiotics , adenylylation , biology , gene , computational biology , biosynthesis , microbiology and biotechnology , genetics
Natural products are a major source of new antibiotics. Here we utilize biosynthetic instructions contained within metagenome‐derived congener biosynthetic gene clusters (BGCs) to guide the synthesis of improved antibiotic analogues. Albicidin and cystobactamid are the first members of a new class of broad‐spectrum ρ‐aminobenzoic acid (PABA)‐based antibiotics. Our search for PABA‐specific adenylation domain sequences in soil metagenomes revealed that BGCs in this family are common in nature. Twelve BGCs that were bio‐informatically predicted to encode six new congeners were recovered from soil metagenomic libraries. Synthesis of these six predicted structures led to the identification of potent antibiotics with changes in their spectrum of activity and the ability to circumvent resistance conferred by endopeptidase cleavage enzymes.