Abstract
Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Clostridioides difficile / drug effects
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Crystallography, X-Ray
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Enterococcus / drug effects
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Escherichia coli Proteins / biosynthesis
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Escherichia coli Proteins / chemistry
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Female
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Gram-Positive Bacterial Infections / drug therapy
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Male
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Mice
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Structure
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Peptide Elongation Factor Tu / chemistry
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Peptides, Cyclic / chemical synthesis*
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / pharmacology
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Protein Synthesis Inhibitors / chemical synthesis
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Protein Synthesis Inhibitors / chemistry
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Protein Synthesis Inhibitors / pharmacology
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Rats
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Rats, Sprague-Dawley
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Staphylococcus aureus / drug effects
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Streptococcus pyogenes / drug effects
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology
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Transcription, Genetic / drug effects
Substances
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Anti-Bacterial Agents
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Escherichia coli Proteins
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Peptides, Cyclic
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Protein Synthesis Inhibitors
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Thiazoles
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thiomuracin A
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Peptide Elongation Factor Tu