Examining the Role of Conformational Rigidity to Antibacterial Activity via Side-Chain Crosslinking of Amphiphilic...

Structure-function relationship studies are a pivotal part of the antimicrobial drug development pipeline. Compared with the extensive studies undertaken to understand structural parameters such as charge and hydrophobicity using peptides and peptidomimetics, only a few reports are available on the effect of structural constraints. In the current work, aromatic oligoamides with a flexible conformation were chosen for the antimicrobial design and structure-function correlation studies. The effect of conformational rigidity on antibacterial activity was examined after side-chain crosslinking. Cationic and hydrophobic groups on adjacent aromatic rings of the oligoamide sequence provided an amphiphilic topology to the molecules, and SC-XRD studies confirmed the molecular design. The antimicrobial activity of the molecules against Gram-negative and Gram-positive bacterial strains was examined considering the effect of conformational freedom, size, charge, ratio of hydrophobic to cationic side chains, and the nature of the cationic group. Compared to the flexible analogs, the molecule with restricted bond rotations could not display higher antimicrobial activity. Our results indicate that conformational rigidity may not be a decisive factor for these aromatic oligoamides for antibacterial action when other controlling structural parameters such as charge and hydrophobicity are present.