biostudies-literatureSingh JNational Cancer InstituteNCI NIH HHS18302-18313https://www.ebi.ac.uk/biostudies/studies/S-EPMC12772433biostudies-literatureUnknown90(51)A new vancomycin C-terminus modification is detailed that improves antimicrobial activity, especially against vancomycin-resistant organisms. Incorporation of a C-terminus cationic guanidiniocarbonyl-pyrrole (GCP) group reinstates activity against vancomycin-resistant bacteria and further improves activity against sensitive organisms by a mechanism independent of d-Ala-d-Ala binding. The functional effects of the added GCP group are apparent in the behavior of 8a, which exhibited pronounced improvements in activity against vancomycin-resistant bacteria relative to vancomycin (ca. 100-fold) and improved activity against sensitive organisms (ca. 10-fold), where the series (8a-d) displayed a dependence on the linker length (potency: n = 2 > 3 > 4 > 5), most evident against vancomycin-sensitive organisms. When combined with an added CBP peripheral modification, the activity against vancomycin-resistant organisms synergistically improved as much as 3000-fold relative to vancomycin, ca. 30-fold or better relative to 8a, and as much as 10-fold relative to CBP-vancomycin. The beneficial effects are observed with introduction at the C-terminus, but not the N-terminus, and a focused SAR indicates they are structure (e.g., linker length) as well as site specific. These observations, along with mechanistic studies, are consistent with targeting a specific feature in the bacterial cell wall versus a nonspecific role attributable to a cationic modification, especially given its modest pKa (7-8).The Journal of organic chemistryGuanidiniocarbonyl-Pyrrole (GCP) C- and N-Terminus Modifications of Vancomycin.PMC12772433CA041101R01 CA041101Singh JBoger DLChatterjee SfalseGuanidiniocarbonyl-Pyrrole (GCP) C- and N-Terminus Modifications of Vancomycin.A new vancomycin C-terminus modification is detailed that improves antimicrobial activity, especially against vancomycin-resistant organisms. Incorporation of a C-terminus cationic guanidiniocarbonyl-pyrrole (GCP) group reinstates activity against vancomycin-resistant bacteria and further improves activity against sensitive organisms by a mechanism independent of d-Ala-d-Ala binding. The functional effects of the added GCP group are apparent in the behavior of 8a, which exhibited pronounced improvements in activity against vancomycin-resistant bacteria relative to vancomycin (ca. 100-fold) and improved activity against sensitive organisms (ca. 10-fold), where the series (8a-d) displayed a dependence on the linker length (potency: n = 2 > 3 > 4 > 5), most evident against vancomycin-sensitive organisms. When combined with an added CBP peripheral modification, the activity against vancomycin-resistant organisms synergistically improved as much as 3000-fold relative to vancomycin, ca. 30-fold or better relative to 8a, and as much as 10-fold relative to CBP-vancomycin. The beneficial effects are observed with introduction at the C-terminus, but not the N-terminus, and a focused SAR indicates they are structure (e.g., linker length) as well as site specific. These observations, along with mechanistic studies, are consistent with targeting a specific feature in the bacterial cell wall versus a nonspecific role attributable to a cationic modification, especially given its modest pKa (7-8).2025-01-01T00:00:00Z2025 Dec2026-06-06T10:56:39.738Z2026-05-29T03:13:02.869ZS-EPMC127724334138103910.1021/acs.joc.5c02760