Abstract
Here we present a natural product discovery approach, whereby structures are bioinformatically predicted from primary sequence and produced by chemical synthesis (synthetic-bioinformatic natural products, syn-BNPs), circumventing the need for bacterial culture and gene expression. When we applied the approach to nonribosomal peptide synthetase gene clusters from human-associated bacteria, we identified the humimycins. These antibiotics inhibit lipid II flippase and potentiate β-lactam activity against methicillin-resistant Staphylococcus aureus in mice, potentially providing a new treatment regimen.
MeSH terms
-
Anti-Bacterial Agents / chemical synthesis
-
Anti-Bacterial Agents / chemistry
-
Anti-Bacterial Agents / isolation & purification*
-
Anti-Bacterial Agents / pharmacology*
-
Biological Products / chemical synthesis
-
Biological Products / chemistry
-
Biological Products / isolation & purification*
-
Biological Products / pharmacology*
-
Drug Discovery / methods*
-
Humans
-
Lipopeptides / chemical synthesis
-
Lipopeptides / chemistry
-
Lipopeptides / genetics
-
Lipopeptides / pharmacology
-
Methicillin-Resistant Staphylococcus aureus / drug effects*
-
Methicillin-Resistant Staphylococcus aureus / enzymology
-
Microbial Sensitivity Tests
-
Microbiota / genetics*
-
Molecular Conformation
-
Peptide Synthases / genetics
-
beta-Lactams / agonists
-
beta-Lactams / metabolism
Substances
-
Anti-Bacterial Agents
-
Biological Products
-
Lipopeptides
-
beta-Lactams
-
humimycin A
-
humimycin B
-
Peptide Synthases
-
non-ribosomal peptide synthase
Associated data
-
PubChem-Substance/318018254
-
PubChem-Substance/318018255