Resistance Phenotypes Mediated by Aminoacyl-Phosphatidylglycerol Synthases
Resistance Phenotypes Mediated by Aminoacyl-Phosphatidylglycerol Synthases
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DOI：
10.1128/jb.06576-11
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发表时间：
2012-03-01
影响因子：
3.2
通讯作者：
Moser, Juergen
中科院分区：
文献类型：
--
作者：
Arendt, Wiebke;Hebecker, Stefanie;Moser, Juergen
磷脂酰甘油（PG）与丙氨酸或赖氨酸的氨酰化氨酰磷脂酰甘油脱氢酶（aaPGS）催化，使各种生物体对抗菌剂的敏感性降低。本研究利用铜绿假单胞菌嵌合突变株产生赖氨酰-磷脂酰甘油（L-PG），而不是天然存在的丙氨酰-磷脂酰甘油（A-PG），研究对细菌耐药性的影响。在总共存在七种抗微生物剂（β-内酰胺、脂肽抗生素、阳离子抗微生物肽[CAMP]）的情况下研究了这种人工磷脂组合物的后果，以定量评估A-PG取代的效果（用L-PG、L-PG和A-PG，增加的A-PG水平）。对于所采用的革兰氏阴性铜绿假单胞菌模型系统，排他性的电荷排斥机制并不能解释由于PG修饰而导致的抗菌药物敏感性减弱。此外，九个orthopaaPGS酶的特异性进行了实验测定。新表征的蛋白质序列允许建立一组重要的A-PG合酶序列，其与相关的L-PG合成酶组进行生物信息学比较。该分析揭示了A-PG和L-PG脱氢酶进化的多样性起源，因为单个酶的特异性并不反映在特征性序列基序方面。这一发现与潜在aaPGS抑制剂的未来开发相关。
The specific aminoacylation of the phospholipid phosphatidylglycerol (PG) with alanine or with lysine catalyzed by aminoacylphosphatidylglycerol synthases (aaPGS) was shown to render various organisms less susceptible to antibacterial agents. This study makes use of Pseudomonas aeruginosa chimeric mutant strains producing lysyl-phosphatidylglycerol (L-PG) instead of the naturally occurring alanyl-phosphatidylglycerol (A-PG) to study the resulting impact on bacterial resistance. Consequences of such artificial phospholipid composition were studied in the presence of an overall of seven antimicrobials (beta-lactams, a lipopeptide antibiotic, cationic antimicrobial peptides [CAMPs]) to quantitatively assess the effect of A-PG substitution (with L-PG, L-PG and A-PG, increased A-PG levels). For the employed Gram-negative P. aeruginosa model system, an exclusive charge repulsion mechanism does not explain the attenuated antimicrobial susceptibility due to PG modification. Additionally, the specificity of nine orthologous aaPGS enzymes was experimentally determined. The newly characterized protein sequences allowed for the establishment of a significant group of A-PG synthase sequences which were bioinformatically compared to the related group of L-PG synthesizing enzymes. The analysis revealed a diverse origin for the evolution of A-PG and L-PG synthases, as the specificity of an individual enzyme is not reflected in terms of a characteristic sequence motif. This finding is relevant for future development of potential aaPGS inhibitors.