Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA.
ChemMedChem. 2013 Aug;8(8):1394-402. doi: 10.1002/cmdc.201300173. Epub 2013 Jun 18.
Cyclic lipopeptides derived from the fusaricidin/LI-F family of naturally occurring antibiotics represent particularly attractive candidates for the development of new antibacterial agents. In comparison with natural products, these derivatives may offer better stability under physiologically relevant conditions and lower nonspecific toxicity, while preserving their antibacterial activity. In this study we assessed the ability of cyclic lipodepsipeptide 1 and its analogues--amide 2, N-methylamide 3, and linear peptide 4--to interact with the cytoplasmic membranes of selected Gram-positive bacteria. We also investigated their bacteriostatic/bactericidal modes of action and in vivo potency by using a Galleria mellonella model of MRSA infection. Cyclic lipopeptides 1 and 2 depolarize the cytoplasmic membranes of Gram-positive bacteria in a concentration-dependent manner. The degree of membrane depolarization was influenced by the structural and physical properties of 1 and 2, with the more flexible and hydrophobic peptide 1 being most efficient. However, membrane depolarization does not correlate with bacterial cell lethality, suggesting that membrane-targeting activity is not the main mode of action for this class of antibacterial peptides. Conversely, substitution of the depsipeptide bond in 1 with an N-methylamide bond in 3, or its hydrolysis to peptide 4, lead to a complete loss of antibacterial activity and indicate that the conformation of cyclic lipopeptides plays a role in their antibacterial activities. Cyclic lipopeptides 1 and 2 are also capable of improving the survival of G. mellonella larvae infected with MRSA at varying efficiencies, reflecting their in vitro activities. Gaining more insight into the structure-activity relationship and mode of action of these cyclic lipopeptides may enable the development of new antibiotics of this class with improved antibacterial activity.
天然存在的抗生素 Fusaricidin/LI-F 家族衍生的环状脂肽代表了开发新型抗菌剂的特别有吸引力的候选物。与天然产物相比，这些衍生物在生理相关条件下可能具有更好的稳定性和较低的非特异性毒性，同时保留其抗菌活性。在这项研究中，我们评估了环状脂二肽 1 及其类似物——酰胺 2、N-甲基酰胺 3 和线性肽 4——与选定革兰氏阳性菌细胞质膜相互作用的能力。我们还通过使用金黄色葡萄球菌感染的家蚕模型研究了它们的抑菌/杀菌作用模式和体内效力。环状脂肽 1 和 2 以浓度依赖的方式使革兰氏阳性菌的细胞质膜去极化。1 和 2 的结构和物理性质影响膜去极化的程度，其中更灵活和疏水性的肽 1 最有效。然而，膜去极化与细菌细胞致死性无关，表明膜靶向活性不是这类抗菌肽的主要作用模式。相反，在 3 中用 N-甲基酰胺键代替 1 中的脂肽键，或水解为肽 4，导致抗菌活性完全丧失，并表明环状脂肽的构象在其抗菌活性中起作用。环状脂肽 1 和 2 还能够以不同的效率提高感染金黄色葡萄球菌的家蚕幼虫的存活率，反映了它们的体外活性。深入了解这些环状脂肽的结构-活性关系和作用模式可能有助于开发具有改善抗菌活性的此类新型抗生素。
