Synthesis and Biological Evaluation of Analogues of the Antibiotic Pantocin B

• Published in: Journal of the American Chemical Society Vol. 123; no. 41; pp. 9935 - 9946
• Main Authors: Sutton, Amanda E, Clardy, Jon
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.10.2001; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Chemistry; Chemistry, Multidisciplinary; Erwinia - drug effects; Erwinia - metabolism; Glycine - chemical synthesis; Glycine - pharmacokinetics; Glycine - pharmacology; Malates - chemical synthesis; Malates - pharmacokinetics; Malates - pharmacology; Microbial Sensitivity Tests; Physical Sciences; Science & Technology; Structure-Activity Relationship; STRAINS; HERBICOLA; ACID
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja003770j

Strains of the bacteria Erwinia herbicola produce antibiotics that effectively control E. amylovora, the bacterial pathogen responsible for the plant disease fire blight. Pantocin B was the first of these antibiotics to be characterized, and a flexible synthesis of various analogues is reported. Embedded in the “pseudo-tripeptide” backbone of pantocin B are a methylenediamine and a methyl sulfone, both unusual structural features in natural products. The peptidic nature of pantocin B facilitated a series of structure−activity relationship studies that probed the roles of these functional groups in determining the biological activity of pantocin B. A clear demarcation of the roles between the N- and C-terminal portions of the antibiotic was determined as a result of the structure−activity relationship studies. The N-terminal l-alanyl group is needed for cellular import but not for interaction with the intracellular target, the arginine biosynthetic enzyme N-acetylornithine aminotransferase. The methylenediamine and methyl sulfone portions were found to be essential for antibiotic activity, presumably due to extensive interactions with N-acetylornithine aminotransferase.