Extensive Structure–Activity Relationship Study of Albicidin's C‐Terminal Dipeptidic p‐Aminobenzoic Acid Moiety

Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity, particularly against Gram‐negative bacteria, turns it into a promising lead structure for an antibacterial drug. Hence, structure–activity relationship studies are key for the in‐depth understanding of structural features/moieties affecting gyrase inhibition, antibacterial activity and overcoming resistance. The 27 newly synthesized albicidins give profound insights into possibilities for variations of the C‐terminus. Furthermore, in the present study, a novel derivative has been identified as overcoming resistance posed by the Klebsiella‐protease AlbD. Structural modifications include, for example, azahistidine replacing the previous instable cyanoalanine as the central amino acid, as well as a triazole amide bond isostere between building blocks D and E. 27 newly synthesized albicidins give profound insights into possibilities for variations of the C‐terminus. In the present study a novel derivative has been identified as overcoming resistance posed by the Klebsiella‐protease AlbD. Structural modifications include, for example, azahistidine replacing the previous instable cyanoalanine as the central amino acid and a triazole amide bond isostere between building blocks D and E (see graphic).