In this article, published in Chemical Science, members of the James S. Nowick group show that the antibiotic teixobactin is a promising drug candidate against drug-resistant pathogens, such as MRSA and VRE, but forms insoluble gels that may limit intravenous administration. O-Acyl isopeptide prodrug analogues of teixobactin circumvent the problem of gel formation while retaining antibiotic activity. The teixobactin prodrug analogues contain ester linkages between Ile6 and Ser7, Ile2 and Ser3, or between both Ile6 and Ser7 and Ile2 and Ser3.
Upon exposure to physiological pH, the prodrug analogues undergo clean conversion to the corresponding amides, with half-lives between 13 and 115 min. Prodrug analogues containing lysine, arginine, or leucine at position 10 exhibit good antibiotic activity against a variety of Gram-positive bacteria while exhibiting little or no cytotoxicity or hemolytic activity. Because O-acyl isopeptide prodrug analogues of teixobactin exhibit clean conversion to the corresponding teixobactin analogues with reduced propensity to form gels, it is anticipated that teixobactin prodrugs will be superior to teixobactin as drug candidates.
Isobactins: O-Acyl Isopeptide Prodrugs of Teixobactin and Teixobactin Derivatives
Chelsea R. Jones, Gretchen Guaglianone, Grant H. Lai, and James S. Nowick
Chem. Sci., 2022, 13, 13110-13116
The Nowick Group