D24

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.

Synthetic musks (SMs) with pleasant odor have been extensively used in personal care products. SMs are emerging contaminants due to the wide detection in human breast milk and blood, and even caused miscarriage to pregnant women. Aiming at this, the two-dimensional quantitative structure-activity relationship (2D-QSAR) coupling with three-dimensional quantitative structure-activity relationship (3D-QSAR) methods were first used to analyze the SM-induced risk of miscarriage in pregnant women, and the above two models were used to mutually authenticate each other. It was found that the critical volume, melting point and heat of formation of SMs were the key descriptors leading to miscarriage. In addition, the adverse outcome pathway (AOP) was used to assess the miscarriage risk of selected SMs and the environment-friendly SM derivatives with desired functional properties designed in previous studies. Results showed that the miscarriage risk of musk ketone derivative (M27) was reduced by approximately three times than that of MK. The miscarriage risk of galaxolide derivatives (i.e., D6 and D24) were about six times lower than that of galaxolide, which further confirmed that the theoretically designed SMs derivatives can effectively reduce the risk of miscarriage in pregnant women. This study provides a comprehensive analysis of the mechanism of SM-induced miscarriage, and provides an accurate and rapid theoretical evaluation method for the future risk assessment of SM-induced miscarriage.