Metagenome-Guided Analogue Synthesis Yields Improved Gram-Negative-Active Albicidin- and Cystobactamid-Type Antibiotics
Dr. Zongqiang Wang
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
These authors contributed equally to this work.
Search for more papers by this authorDr. Amanda Kasper
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
These authors contributed equally to this work.
Search for more papers by this authorRabia Mehmood
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
Search for more papers by this authorMelinda Ternei
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
Search for more papers by this authorDr. Shaogang Li
Department of Medicine, Center for Emerging and Re-emerging Pathogens, Rutgers University—New Jersey Medical School, Newark, NJ, 07103 USA
Search for more papers by this authorProf. Joel S. Freundlich
Department of Medicine, Center for Emerging and Re-emerging Pathogens, Rutgers University—New Jersey Medical School, Newark, NJ, 07103 USA
Search for more papers by this authorCorresponding Author
Prof. Sean F. Brady
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
Search for more papers by this authorDr. Zongqiang Wang
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
These authors contributed equally to this work.
Search for more papers by this authorDr. Amanda Kasper
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
These authors contributed equally to this work.
Search for more papers by this authorRabia Mehmood
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
Search for more papers by this authorMelinda Ternei
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
Search for more papers by this authorDr. Shaogang Li
Department of Medicine, Center for Emerging and Re-emerging Pathogens, Rutgers University—New Jersey Medical School, Newark, NJ, 07103 USA
Search for more papers by this authorProf. Joel S. Freundlich
Department of Medicine, Center for Emerging and Re-emerging Pathogens, Rutgers University—New Jersey Medical School, Newark, NJ, 07103 USA
Search for more papers by this authorCorresponding Author
Prof. Sean F. Brady
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065 USA
Search for more papers by this authorAbstract
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.
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