Investigation of Isobactin Analogues of Teixobactin.
ACS Med Chem Lett
; 15(7): 1136-1142, 2024 Jul 11.
Article
in En
| MEDLINE
| ID: mdl-39015269
ABSTRACT
Although teixobactin is a promising antibiotic drug candidate against Gram-positive bacteria, it aggregates to form gels that may limit intravenous administration. We previously reported O-acyl isopeptide prodrugs of teixobactin analogues that address the problem of gel formation while retaining antibiotic activity. We termed these compounds isobactins. In the current Letter, we present nine new isobactin analogues that exhibit a reduced propensity to form gels in aqueous conditions while maintaining potent antibiotic activity against MRSA, VRE, and other Gram-positive bacteria. These isobactin analogues contain commercially available amino acid residues at position 10, replacing the synthetically challenging l-allo-enduracididine residue that is present in teixobactin. The isobactins undergo clean conversion to their corresponding teixobactin analogues at physiological pH and exhibit little to no hemolytic activity or cytotoxicity. Because isobactin analogues exhibit enhanced solubility, delayed gel formation, and are more synthetically accessible, it is anticipated that isobactin prodrug analogues may be superior drug candidates to teixobactin.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
ACS Med Chem Lett
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Estados Unidos