title: Antibacterial and Solubility Optimization of Thiomuracin A.
abstract: Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogues in the Northern region (C2-C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., 3) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster C. difficile models of disease. Optimal efficacy in the hamster model of C. difficile was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LaMarche
authors.affiliation: Infectious Disease Area, Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Leeds
authors.forename: Jason
authors.initials: J
authors.lastname: Brewer
authors.forename: Karl
authors.initials: K
authors.lastname: Dean
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Infectious Disease Area, Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Dzink-Fox
authors.forename: Gabe
authors.initials: G
authors.lastname: Gamber
authors.forename: Akash
authors.initials: A
authors.lastname: Jain
authors.forename: Ryan
authors.initials: R
authors.lastname: Kerrigan
authors.affiliation: Natural Products Unit, Novartis Institutes for Biomedical Research , Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel
authors.forename: Kwangho
authors.initials: K
authors.lastname: Lee
authors.forename: Franco
authors.initials: F
authors.lastname: Lombardo
authors.affiliation: Infectious Disease Area, Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
authors.forename: David
authors.initials: D
authors.lastname: McKenney
authors.affiliation: Infectious Disease Area, Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
authors.forename: Georg
authors.initials: G
authors.lastname: Neckermann
authors.affiliation: Infectious Disease Area, Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
authors.forename: Colin
authors.initials: C
authors.lastname: Osborne
authors.forename: Deborah
authors.initials: D
authors.lastname: Palestrant
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patane
authors.forename: Elin M
authors.initials: EM
authors.lastname: Rann
authors.forename: Zachary
authors.initials: Z
authors.lastname: Robinson
authors.affiliation: Natural Products Unit, Novartis Institutes for Biomedical Research , Basel, Switzerland.
authors.forename: Esther
authors.initials: E
authors.lastname: Schmitt
authors.forename: Travis
authors.initials: T
authors.lastname: Stams
authors.affiliation: Infectious Disease Area, Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
authors.forename: Stacey
authors.initials: S
authors.lastname: Tiamfook
authors.affiliation: Infectious Disease Area, Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
authors.forename: Donghui
authors.initials: D
authors.lastname: Yu
authors.forename: Lewis
authors.initials: L
authors.lastname: Whitehead
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects*; D003015:Clostridium Infections / Q000188:drug therapy*; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D013844:Thiazoles; C576049:thiomuracin A