Antibiotic optimization and chemical structure stabilization of thiomuracin A.
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.
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States. matthew.lamarche@novartis.com
Matthew J
MJ
LaMarche
Jennifer A
JA
Leeds
Joanne
J
Dzink-Fox
Eric
E
Gangl
Philipp
P
Krastel
Georg
G
Neckermann
Deborah
D
Palestrant
Michael A
MA
Patane
Elin M
EM
Rann
Stacey
S
Tiamfook
Donghui
D
Yu
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016360:Clostridioides difficile / Q000187:drug effects; D018360:Crystallography, X-Ray; D016983:Enterococcus / Q000187:drug effects; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000096:biosynthesis / Q000737:chemistry; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010444:Peptide Elongation Factor Tu / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013211:Staphylococcus aureus / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D010456:Peptides, Cyclic; D011500:Protein Synthesis Inhibitors; D013844:Thiazoles; C576049:thiomuracin A; D010444:Peptide Elongation Factor Tu