To combat antimicrobial resistance (AMR), it is essential to have a good understanding of the infection mechanisms, particularly those concerning the interaction between anti-infective agents and pathogen targets. Within this context, antimicrobial peptides (AMPs) are emerging as promising therapeutic alternatives amid the pressing global issue of AMR. Their appeal stems from straightforward yet effective mechanisms of action, wide-ranging efficacy, adaptability for structural modifications through versatile peptide engineering techniques, and cost-effective production.

Ctn[15-34]^1,2, a segment at the C-terminal of crotalicidin (Ctn), a cathelicidin sourced from a South American pit viper, stands as a candidate antimicrobial and antitumoral peptide. Notably, it exhibits significantly greater stability in human serum compared to its parent Ctn. This work delves into a series of topoisomers of both Ctn and Ctn[15-34], including their retro, enantio, and retroenantio versions to uncover the structural prerequisites for their activity³. Remarkably, all topoisomers demonstrate comparable in vitro activity to their cognate sequences against gram-negative bacteria and tumor cells, albeit slightly elevated toxicity toward normal cells. Furthermore, their heightened stability in human fluids enhances their prospects for future exploration. Hence Ctn[15-34] and Ctn retroenantio, the best in vitro performers, were selected for an in vivo efficacy evaluation in a murine model of Acinetobacter baumannii systemic infection. Unexpectedly, all animals treated with retroenantio peptide succumbed within 8 h. In contrast, for Ctn[15-34] divergent survival outcomes between genders were found, females outlasting males by ~ 1 day.