Dodecapeptides derived from human cathelicidin with potent activity against carbapenem-resistant Acinetobacter baumannii

The increasing infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) poses a serious threat to global public health. Antimicrobial peptides (AMPs) are alternatives to conventional antibiotics in combating superbugs. However, discovering AMPs with low synthesis costs and strong antibacterial effects against CRAB is challenging. In this study, we synthesized 28 dodecapeptides for bactericidal assessment by site mutation and all-hydrocarbon stapling on the basis of the antibacterial core of human cathelicidin. The linear derivative d12 (Q5RD9I-KR12) and the i, i + 4 stapled peptide d24, which was generated by substituting Val⁴ and Lys⁸ of d12 to staples, stood out among the candidates. These short AMPs efficiently bound to bacterial membrane and penetrated it in a lipid A-dependent manner, resulting in low minimal inhibitory concentrations to inactivate CRAB clinical isolates (2.5–20 μg/mL). The CRAB infection mouse models of irradiation-assisted local pulmonary infection and intra-abdominal sepsis revealed that treatment with d12 and d24 significantly eliminated CRAB in vivo and thereby increased mouse survival. Owing to its improved proteolytic resistance, d24 outperformed d12 in suppressing intra-abdominal CRAB infection. The excellent antibacterial effects, good biocompatibility, and facile synthesis make d12 and d24 promising candidates to curb CRAB infections in different application scenarios.