Pseudodesmin A (PSD) is a cyclic lipodepsipeptide produced by Pseudomonas that kills certain bacteria at MIC_1/2 in the single micromolar range, probably by permeabilizing their cellular membranes. Synthetic PSD variants, where the native decanoic (C10) acyl chain is varied in length from C4 to C8 and C12 to C14 carbons, were described to be not or less active against a panel of gram-positive strains, as compared to native PSD-C10. Here, we test the membrane-permeabilizing activity of PSD-C4 through PSD-C14 in terms of calcein release from liposomes, which is characterized in detail by the fluorescence-lifetime based leakage assay. Antagonistic concentrations and their chain length dependence agree well for liposome leakage and antimicrobial activity. The optimal chain length is governed by a balance between membrane partitioning (favoring longer chains) and the local perturbation or “damage” inflicted by a membrane-bound molecule (weakening for longer chains). Local perturbation, in turn, may involve at least two modes of action. Asymmetry stress between outer and inner leaflet builds up as the lipopeptides enter the outer leaflet and when it reaches a system-specific stability threshold, it causes a transient membrane failure that allows for the flip of some molecules from the outer to the inner leaflet. This cracking-in may be accompanied by transient, incomplete leakage from the aqueous cores of the liposomes observed, typically, for some seconds or less. The mismatch of the lipopeptide with the lipid leaflet geometry, expressed for example in terms of a spontaneous curvature, has two effects. First, it affects the threshold for transient leakage as described. Second, it controls the rate of equilibrium leakage proceeding as the lipopeptide has reached sufficient local concentrations in both leaflets to form quasi-toroidal defects or pores. Both modes of action, transient and equilibrium leakage, synergize for intermediate chain lengths such as the native, i.e., for PSD-C10. These mechanisms may also account for the reported chain-length dependent specificities of antibiotic action against the target bacteria.

Pseudodesmin A (PSD) 是一种环状脂缩肽，由 假单胞菌在 MIC _1/2杀死某些细菌在单微摩尔范围内，可能是通过透化它们的细胞膜。合成 PSD 变体，其中天然癸酸 (C10) 酰基链的长度从 C4 到 C8 和 C12 到 C14 碳变化，与天然 PSD 相比，对一组革兰氏阳性菌株没有活性或活性较低。 C10. 在这里，我们测试了 PSD-C4 到 PSD-C14 在从脂质体释放钙黄绿素方面的膜通透活性，其详细特征是基于荧光寿命的泄漏测定。拮抗浓度及其链长依赖性对于脂质体渗漏和抗菌活性非常一致。最佳链长由膜分配（有利于较长链）与膜结合分子造成的局部扰动或“损伤”（较长链弱化）之间的平衡控制。反过来，局部扰动可能涉及至少两种作用模式。当脂肽进入外小叶时，外小叶和内小叶之间的不对称应力会增加，当它达到系统特定的稳定性阈值时，它会导致暂时的膜失效，从而允许一些分子从外小叶翻转到内小叶。这种裂变可能伴随着从观察到的脂质体的水核的短暂的、不完全的泄漏，通常持续数秒或更短时间。脂肽与脂质小叶几何形状的不匹配，例如以自发曲率表示，有两个作用。首先，它会影响所描述的瞬态泄漏阈值。其次，当脂肽在两个小叶中达到足够的局部浓度以形成准环形缺陷或孔时，它控制平衡渗漏进行的速率。两种作用模式，瞬时泄漏和平衡泄漏，对中间链长度（例如天然链，即 PSD-C10）产生协同作用。这些机制也可以解释所报道的针对目标细菌的抗生素作用的链长依赖性特异性。协同中间链长度，例如天然的，即 PSD-C10。这些机制也可以解释所报道的针对目标细菌的抗生素作用的链长依赖性特异性。协同中间链长度，例如天然的，即 PSD-C10。这些机制也可以解释所报道的针对目标细菌的抗生素作用的链长依赖性特异性。