Mohamed Mohamed F, Hamed Maha I, Panitch Alyssa, Seleem Mohamed N
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.
Antimicrob Agents Chemother. 2014 Jul;58(7):4113-22. doi: 10.1128/AAC.02578-14. Epub 2014 May 5.
The seriousness of microbial resistance combined with the lack of new antimicrobials has increased interest in the development of antimicrobial peptides (AMPs) as novel therapeutics. In this study, we evaluated the antimicrobial activities of two short synthetic peptides, namely, RRIKA and RR. These peptides exhibited potent antimicrobial activity against Staphylococcus aureus, and their antimicrobial effects were significantly enhanced by addition of three amino acids in the C terminus, which consequently increased the amphipathicity, hydrophobicity, and net charge. Moreover, RRIKA and RR demonstrated a significant and rapid bactericidal effect against clinical and drug-resistant Staphylococcus isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), linezolid-resistant S. aureus, and methicillin-resistant Staphylococcus epidermidis. In contrast to many natural AMPs, RRIKA and RR retained their activity in the presence of physiological concentrations of NaCl and MgCl2. Both RRIKA and RR enhanced the killing of lysostaphin more than 1,000-fold and eradicated MRSA and VRSA isolates within 20 min. Furthermore, the peptides presented were superior in reducing adherent biofilms of S. aureus and S. epidermidis compared to results with conventional antibiotics. Our findings indicate that the staphylocidal effects of our peptides were through permeabilization of the bacterial membrane, leading to leakage of cytoplasmic contents and cell death. Furthermore, peptides were not toxic to HeLa cells at 4- to 8-fold their antimicrobial concentrations. The potent and salt-insensitive antimicrobial activities of these peptides present an attractive therapeutic candidate for treatment of multidrug-resistant S. aureus infections.
微生物耐药性的严重性以及新型抗菌药物的匮乏，使得人们对开发抗菌肽（AMPs）作为新型治疗药物的兴趣日益浓厚。在本研究中，我们评估了两种短合成肽RRIKA和RR的抗菌活性。这些肽对金黄色葡萄球菌表现出强大的抗菌活性，并且通过在C末端添加三个氨基酸，它们的抗菌效果显著增强，从而增加了两亲性、疏水性和净电荷。此外，RRIKA和RR对临床分离株和耐药金黄色葡萄球菌，包括耐甲氧西林金黄色葡萄球菌（MRSA）、万古霉素中介金黄色葡萄球菌（VISA）、万古霉素耐药金黄色葡萄球菌（VRSA）、耐利奈唑胺金黄色葡萄球菌以及耐甲氧西林表皮葡萄球菌，都表现出显著且快速的杀菌作用。与许多天然AMPs不同，RRIKA和RR在生理浓度的NaCl和MgCl2存在下仍保留其活性。RRIKA和RR均使溶葡萄球菌素的杀菌效果增强了1000倍以上，并在20分钟内根除了MRSA和VRSA分离株。此外，与传统抗生素相比，所呈现的肽在减少金黄色葡萄球菌和表皮葡萄球菌的附着生物膜方面表现更优。我们的研究结果表明，这些肽的杀葡萄球菌作用是通过使细菌膜通透性增加，导致细胞质内容物泄漏和细胞死亡。此外，在抗菌浓度4至8倍的情况下，这些肽对HeLa细胞无毒。这些肽强大且对盐不敏感的抗菌活性使其成为治疗多重耐药金黄色葡萄球菌感染的有吸引力的治疗候选药物。
