Choi Joonhyeok, Jang Ahjin, Yoon Young Kyung, Kim Yangmee
Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea.
Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Korea.
Pharmaceutics. 2021 Oct 27;13(11):1800. doi: 10.3390/pharmaceutics13111800.
Carbapenem-resistant (CRAB) infection has a high mortality rate, making the development of novel effective antibiotic therapeutic strategies highly critical. Antimicrobial peptides can outperform conventional antibiotics regarding drug resistance and broad-spectrum activity. PapMA, an 18-residue hybrid peptide, containing N-terminal residues of papiliocin and magainin 2, has previously demonstrated potent antibacterial activity. In this study, PapMA analogs were designed by substituting Ala or Phe with Ala, Phe, and Trp. PapMA-3 with Trp showed the highest bacterial selectivity against CRAB, alongside low cytotoxicity. Biophysical studies revealed that PapMA-3 permeabilizes CRAB membrane via strong binding to LPS. To reduce toxicity via reduced antibiotic doses, while preventing the emergence of multi-drug resistant bacteria, the efficacy of PapMA-3 in combination with six selected antibiotics was evaluated against clinical CRAB isolates (C1-C5). At 25% of the minimum inhibition concentration, PapMA-3 partially depolarized the CRAB membrane and caused sufficient morphological changes, facilitating the entry of antibiotics into the bacterial cell. Combining PapMA-3 with rifampin significantly and synergistically inhibited CRAB C4 (FICI = 0.13). Meanwhile, combining PapMA-3 with vancomycin or erythromycin, both potent against Gram-positive bacteria, demonstrated remarkable synergistic antibiofilm activity against Gram-negative CRAB. This study could aid in the development of combination therapeutic approaches against CRAB.
耐碳青霉烯类（CRAB）感染死亡率高，因此开发新型有效的抗生素治疗策略至关重要。抗菌肽在耐药性和广谱活性方面优于传统抗生素。PapMA是一种含有18个残基的杂合肽，包含乳头菌素和蛙皮素2的N端残基，此前已显示出强大的抗菌活性。在本研究中，通过用丙氨酸、苯丙氨酸和色氨酸取代丙氨酸或苯丙氨酸来设计PapMA类似物。含色氨酸的PapMA-3对CRAB表现出最高的细菌选择性，同时细胞毒性较低。生物物理研究表明，PapMA-3通过与脂多糖的强烈结合使CRAB膜通透性增加。为了通过减少抗生素剂量降低毒性，同时防止多重耐药菌的出现，评估了PapMA-3与六种选定抗生素联合使用对临床CRAB分离株（C1-C5）的疗效。在最低抑菌浓度的25%时，PapMA-3使CRAB膜部分去极化并引起足够的形态变化，促进抗生素进入细菌细胞。PapMA-3与利福平联合使用对CRAB C4有显著的协同抑制作用（FICI = 0.13）。同时，PapMA-3与对革兰氏阳性菌有效的万古霉素或红霉素联合使用，对革兰氏阴性CRAB表现出显著的协同抗生物膜活性。本研究有助于开发针对CRAB的联合治疗方法。
