Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University, Jinju, 52828, Republic of Korea.
Primer Biotech Research Center, Jaipuri Colony, Nagole, Hyderabad, Telangana, 500068, India.
Ann Clin Microbiol Antimicrob. 2018 Apr 2;17(1):16. doi: 10.1186/s12941-018-0266-9.
Antibiotic resistance is a defense mechanism, harbored by pathogens to survive under unfavorable conditions. Among several antibiotic resistant microbial consortium, Staphylococcus aureus is one of the most havoc microorganisms. Staphylococcus aureus encodes a unique enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), against which, none of existing antibiotics have been reported.
Computational approaches have been instrumental in designing and discovering new drugs for several diseases. The present study highlights the impact of ginger phytochemicals on Staphylococcus aureus SaHPPK. Herein, we have retrieved eight ginger phytochemicals from published literature and investigated their inhibitory interactions with SaHPPK. To authenticate our work, the investigation proceeds considering the known antibiotics alongside the phytochemicals. Molecular docking was performed employing GOLD and CDOCKER. The compounds with the highest dock score from both the docking programmes were tested for their inhibitory capability in vitro. The binding conformations that were seated within the binding pocket showing strong interactions with the active sites residues rendered by highest dock score were forwarded towards the molecular dynamic (MD) simulation analysis.
Based on molecular dock scores, molecular interaction with catalytic active residues and MD simulations studies, two ginger phytochemicals, gingerenone-A and shogaol have been proposed as candidate inhibitors against Staphylococcus aureus. They have demonstrated higher dock scores than the known antibiotics and have represented interactions with the key residues within the active site. Furthermore, these compounds have rendered considerable inhibitory activity when tested in vitro. Additionally, their superiority was corroborated by stable MD results conducted for 100 ns employing GROMACS package.
Finally, we suggest that gingerenone-A and shogaol may either be potential SaHPPK inhibitors or can be used as fundamental platforms for novel SaHPPK inhibitor development.
抗生素耐药性是一种防御机制，病原体以此在不利条件下生存。在几种抗生素耐药性微生物联合体中，金黄色葡萄球菌是最具破坏力的微生物之一。金黄色葡萄球菌编码一种独特的酶 6-羟甲基-7,8-二氢蝶呤焦磷酸激酶（SaHPPK），针对这种酶，目前尚无报道的抗生素。
计算方法在设计和发现针对几种疾病的新药方面发挥了重要作用。本研究强调了姜科植物化学物质对金黄色葡萄球菌 SaHPPK 的影响。在这里，我们从已发表的文献中检索了八种姜科植物化学物质，并研究了它们与 SaHPPK 的抑制相互作用。为了验证我们的工作，在考虑已知抗生素的同时，还对植物化学物质进行了调查。采用 GOLD 和 CDOCKER 进行分子对接。从两个对接程序中获得最高对接分数的化合物在体外进行了抑制能力测试。将位于结合口袋内、与活性部位残基具有强相互作用并显示出最高对接分数的结合构象提交给分子动力学（MD）模拟分析。
基于分子对接分数、与催化活性残基的分子相互作用以及 MD 模拟研究，提出了两种姜科植物化学物质，姜烯酮-A 和姜辣素，作为金黄色葡萄球菌的候选抑制剂。它们的对接分数高于已知的抗生素，并与活性部位的关键残基相互作用。此外，当在体外进行测试时，这些化合物表现出相当大的抑制活性。此外，使用 GROMACS 包进行 100ns 的稳定 MD 结果进一步证实了它们的优越性。
最后，我们建议姜烯酮-A 和姜辣素可能是潜在的 SaHPPK 抑制剂，也可以作为新型 SaHPPK 抑制剂开发的基础平台。
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