Mukhopadhyay Kasturi, Whitmire William, Xiong Yan Q, Molden Jaime, Jones Tiffanny, Peschel Andreas, Staubitz Petra, Adler-Moore Jill, McNamara Peter J, Proctor Richard A, Yeaman Michael R, Bayer Arnold S
The LA Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Microbiology (Reading). 2007 Apr;153(Pt 4):1187-1197. doi: 10.1099/mic.0.2006/003111-0.
Thrombin-induced platelet microbicidal proteins (e.g. tPMP-1) are small cationic peptides released from mammalian platelets. As the cytoplasmic membrane (CM) is a primary target of tPMPs, distinct CM characteristics are likely to affect the cells' susceptibility profiles. In Staphylococcus aureus, CM surface charge and hydrophobicity are principally determined by the content and distribution of its three major phospholipid (PL) constituents: negatively charged phosphatidylglycerol (PG) and cardiolipin (CL) and positively charged lysyl-PG (LPG). PL composition profiles, and inner vs outer CM leaflet PL distributions, were compared in an isogenic tPMP-susceptible (tPMP(S)) and -resistant (tPMP(R)) S. aureus strain pair (ISP479C vs ISP479R respectively). All PLs were asymmetrically distributed between the outer and inner CM leaflets in both strains. However, in ISP479R, the outer CM leaflet content of LPG was significantly increased vs ISP479C (27.3+/-11.0 % vs 18.6+/-7.0 % respectively; P=0.05). This observation correlated with reduced binding of the cationic proteins cytochrome c, poly-L-lysine, tPMP-1 and the tPMP-1-mimetic peptide, RP1, to tPMP-1(R) whole cells and to model liposomal CMs with LPG content and distribution similar to that of tPMP-1(R) strains. Collectively, selected CM parameters correlated with reduced staphylocidal capacities of tPMP-1 against certain S. aureus strains, including relative increases in outer CM leaflet positive charge and reduced surface binding of cationic molecules. These findings offer new insights into mechanisms of antimicrobial peptide susceptibility and resistance in S. aureus.
凝血酶诱导的血小板杀菌蛋白（如tPMP-1）是从哺乳动物血小板释放的小阳离子肽。由于细胞质膜（CM）是tPMPs的主要靶标，不同的CM特性可能会影响细胞的敏感性。在金黄色葡萄球菌中，CM表面电荷和疏水性主要由其三种主要磷脂（PL）成分的含量和分布决定：带负电荷的磷脂酰甘油（PG）、心磷脂（CL）和带正电荷的赖氨酰-PG（LPG）。在一对同源的对tPMP敏感（tPMP(S)）和耐药（tPMP(R)）的金黄色葡萄球菌菌株（分别为ISP479C和ISP479R）中比较了PL组成概况以及CM内外小叶的PL分布。两种菌株中所有PL在CM内外小叶之间均不对称分布。然而，与ISP479C相比，ISP479R中LPG的CM外小叶含量显著增加（分别为27.3±11.0%和18.6±7.0%；P=0.05）。这一观察结果与阳离子蛋白细胞色素c,聚-L-赖氨酸,tPMP-1和tPMP-1模拟肽RP1与tPMP-1(R)全细胞以及与LPG含量和分布类似于tPMP-1(R)菌株的模型脂质体CM的结合减少相关。总的来说，选定的CM参数与tPMP-1对某些金黄色葡萄球菌菌株的杀葡萄球菌能力降低相关，包括CM外小叶正电荷的相对增加和阳离子分子表面结合的减少。这些发现为金黄色葡萄球菌中抗菌肽敏感性和耐药性机制提供了新的见解。
