Guanidiniocarbonyl-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 <b>8a</b>, 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 (<b>8a</b>-<b>d</b>) displayed a dependence on the linker length (potency: <i>n</i> = 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 <b>8a</b>, 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 p<i>K</i>_a (7-8).