Selecting antibacterial aptamers against the BamA protein in Pseudomonas aeruginosa by incorporating genetic algorithm to optimise computational screening method.
Selecting antibacterial aptamers against the BamA protein in Pseudomonas aeruginosa by incorporating genetic algorithm to optimise computational screening method.
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DOI：
10.1038/s41598-023-34643-5
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发表时间：
2023-05-10
影响因子：
4.6
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中科院分区：
文献类型：
--
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抗生素耐药性是对全球健康的最大威胁之一，导致越来越多的人患有严重疾病或死于曾经很容易用抗生素治愈的感染。铜绿假单胞菌是一种主要的病原体，它迅速产生抗生素耐药性，世卫组织已将这种病原体归类为危重病。DNA适体可以作为一种潜在的候选新的抗菌剂。在这项研究中，我们证明了现有的适体能够影响铜绿假单胞菌的生长。对能够结合革兰氏阴性菌中保守且必需的外膜蛋白BamA的适体进行了计算机筛选。通过局部和全局对接方法对约100个功能性DNA适体与BamA蛋白进行了分子对接。此外，进行遗传算法分析以基于其结合亲和力对适体进行排序。合成与BamA蛋白具有良好结合的适体的顶部命中物以研究其体外抗菌活性。在所有适体中，已知与抗肿瘤药道诺霉素结合的Apt31表现出最高的HADDOCK评分，并导致铜绿假单胞菌生长的显著（p < 0.05）减少。Apt31还诱导膜破坏，导致DNA泄漏。因此，计算筛选可导致以高亲和力结合所需活性位点的适体的鉴定。
Antibiotic resistance is one of the biggest threats to global health resulting in an increasing number of people suffering from severe illnesses or dying due to infections that were once easily curable with antibiotics. Pseudomonas aeruginosa is a major pathogen that has rapidly developed antibiotic resistance and WHO has categorised this pathogen under the critical list. DNA aptamers can act as a potential candidate for novel antimicrobial agents. In this study, we demonstrated that an existing aptamer is able to affect the growth of P. aeruginosa. A computational screen for aptamers that could bind to a well-conserved and essential outer membrane protein, BamA in Gram-negative bacteria was conducted. Molecular docking of about 100 functional DNA aptamers with BamA protein was performed via both local and global docking approaches. Additionally, genetic algorithm analysis was carried out to rank the aptamers based on their binding affinity. The top hits of aptamers with good binding to BamA protein were synthesised to investigate their in vitro antibacterial activity. Among all aptamers, Apt31, which is known to bind to an antitumor, Daunomycin, exhibited the highest HADDOCK score and resulted in a significant (p < 0.05) reduction in P. aeruginosa growth. Apt31 also induced membrane disruption that resulted in DNA leakage. Hence, computational screening may result in the identification of aptamers that bind to the desired active site with high affinity.
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