Novel Cecropin-4 Derived Peptides against Methicillin-Resistant Staphylococcus aureus.
Novel Cecropin-4 Derived Peptides against Methicillin-Resistant Staphylococcus aureus.
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新型天蚕素 4 衍生肽对抗耐甲氧西林金黄色葡萄球菌
DOI：
10.3390/antibiotics10010036
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发表时间：
2021-01-01
期刊：
影响因子：
--
通讯作者：
Mylonakis E
中科院分区：
文献类型：
--
作者：
Peng J;Mishra B;Khader R;Felix L;Mylonakis E
微生物耐药性的增加，加上缺乏新的抗菌剂的发现，导致研究人员重新关注抗菌肽（AMP）作为新的治疗候选物。值得注意的是，毒性较低的天蚕素已经获得了潜在的抗菌剂开发的广泛关注。然而，窄活性谱和长序列仍然是这种方法的主要限制。在这项研究中，我们截断和修改天蚕素4（41个氨基酸），通过改变电荷和疏水性平衡，以获得更小的AMP。衍生肽C18（16个氨基酸）表现出对革兰氏阴性菌和革兰氏阳性菌以及酵母菌的高抗菌活性。此外，C18对耐甲氧西林金黄色葡萄球菌（MRSA）的最小抑菌浓度（MIC）为4 µg/mL，与达托霉素具有协同作用，部分抑制浓度指数（FICI）值为0.313。与传统的天蚕素类似，C18在32 µg/mL时改变膜电位，增加流动性，并导致膜破裂。重要的是，C18在10 × MIC下在20分钟内消除了99%的持留菌，并在32和16 µg/mL下将生物膜粘附降低了约40%和35%。此外，C18在7.8 μM时与DNA具有较强的结合能力，并使agrA、fnb-A和clf-1等毒力因子基因的表达下调5倍以上（p < 0.05）。有趣的是，在Galleria mellonella模型中，C18以8 mg/kg的单剂量在感染后120小时内拯救了超过80%的感染MRSA的幼虫（p < 0.05）。总之，本研究为天蚕素转化为小肽提供了参考，并将C18作为一种有吸引力的治疗候选药物开发用于治疗严重的MRSA感染。
Increasing microbial resistance, coupled with a lack of new antimicrobial discovery, has led researchers to refocus on antimicrobial peptides (AMPs) as novel therapeutic candidates. Significantly, the less toxic cecropins have gained widespread attention for potential antibacterial agent development. However, the narrow activity spectrum and long sequence remain the primary limitations of this approach. In this study, we truncated and modified cecropin 4 (41 amino acids) by varying the charge and hydrophobicity balance to obtain smaller AMPs. The derivative peptide C18 (16 amino acids) demonstrated high antibacterial activity against Gram-negative and Gram-positive bacteria, as well as yeasts. Moreover, C18 demonstrated a minimal inhibitory concentration (MIC) of 4 µg/mL against the methicillin-resistant Staphylococcus aureus (MRSA) and showed synergy with daptomycin with a fractional inhibition concentration index (FICI) value of 0.313. Similar to traditional cecropins, C18 altered the membrane potential, increased fluidity, and caused membrane breakage at 32 µg/mL. Importantly, C18 eliminated 99% persisters at 10 × MIC within 20 min and reduced the biofilm adherence by ~40% and 35% at 32 and 16 µg/mL. Besides, C18 possessed a strong binding ability with DNA at 7.8 μM and down-regulated the expression of virulence factor genes like agrA, fnb-A, and clf-1 by more than 5-fold (p < 0.05). Interestingly, in the Galleria mellonella model, C18 rescued more than 80% of larva infected with the MRSA throughout 120-h post-infection at a single dose of 8 mg/kg (p < 0.05). In conclusion, this study provides a reference for the transformation of cecropin to derive small peptides and presents C18 as an attractive therapeutic candidate to be developed to treat severe MRSA infections.
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影响因子：
15
作者：
Mishra B;Wang G
通讯作者：
Wang G
影响因子：
33.9
作者：
Kourtis, Athena P.;Hatfield, Kelly;Cardo, Denise
通讯作者：
Cardo, Denise
影响因子：
13.6
作者：
Nagarajan, Deepesh;Roy, Natasha;Chandra, Nagasuma
通讯作者：
Chandra, Nagasuma
影响因子：
--
作者：
Hidayat, Levita K.;Hsu, Donald I.;Wong-Beringer, Annie
通讯作者：
Wong-Beringer, Annie
DOI：
10.1073/pnas.1904700116
发表时间：
2019-08-13
影响因子：
11.1
作者：
Kim, Wooseong;Zou, Guijin;Mylonakis, Eleftherios
通讯作者：
Mylonakis, Eleftherios