A review on small molecular mimics of antimicrobial peptides with an emphasis on the structure–activity relationship perspective

The rapid emergence of antibiotic resistance in bacteria has created an alarming situation in public health, which remains a major concern worldwide. In addition, the biofilm-forming ability of bacteria has further complicated the situation in the current scenario. To address these global clinical threats, small molecular mimics of antimicrobial peptides (AMPs) have emerged as a promising class of antibacterial agents. These molecules primarily kill bacteria by targeting their membranes, making it difficult for bacteria to develop resistance against them. Some of these classes of molecules have already been reported as potent antibiofilm agents and have demonstrated promising in vivo efficacy. In this review, we aim to provide an overview of this class of molecules with a focus on recent developments in the field. Different classes of small molecular AMP mimics are discussed with an emphasis on design rationale and the structure–activity-relationship (SAR) facet. The role of different parameters (such as hydrophobicity, charge, structural flexibility/rigidity, and spatial distribution of hydrophobicity) that control their physico-chemical property and thereby the antibacterial activity and toxicity is illustrated. Moreover, the antibiofilm ability and in vivo efficacy of this class of molecules are described to elucidate the possibility of being developed as future antibacterial drugs. Finally, the challenges associated with this class of molecules for their clinical translation as antibacterial therapy are discussed along with future perspectives for advancing the field.