据台湾《联合晚报》报道,台湾“中央研究院”院长翁启惠和基因体研究中心副研究员马彻共同领导的研究团队,成功解构了细菌的保护屏障,突破了苦恼全球科学家20年的“细菌谜团”。
长久以来,医药界一直以转胜肽酶为标的,设计出一系列对抗细菌的抗生素,其中最有名的就是盘尼西林;然而,随着细菌抗药性的增加,这类抗生素的威力大不如前,人类在遭受各种细菌的强大威胁时,也逐渐面临无药可用的窘境。
马彻说,虽然科学家清楚知道透过抑制转醣酶来开发新一代抗生素,但因对转醣酶的结构及作用机制不清楚,20年来进展有限。“中研院”基因体研究中心近年来针对转醣酶进行一系列研究,成功利用X光绕射方法,清晰解构出金黄色葡萄球菌细胞壁上转醣酶及其受质的复合结构。今后只要设计出可阻断转醣酶继续作用下去的小分子药物,就能开发出可杀死细菌的新一代抗生素。
据报道,这项重要的研究发现,发表在“美国国家科学院期刊”最新一期刊物中,引起全球科学界高度重视。翁启惠认为,这是未来解决具抗药性细菌的利器,很有前景。
doi:10.1073/pnas.1203900109
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Crystal structure of Staphylococcus aureus transglycosylase in complex with a lipid II analog and elucidation of peptidoglycan synthesis mechanism
Chia-Ying Huang, Hao-Wei Shih, Li-Ying Lin, Yi-Wen Tien, Ting-Jen Rachel Cheng, Wei-Chieh Cheng, Chi-Huey Wong, and Che Ma
Bacterial transpeptidase and transglycosylase on the surface are essential for cell wall synthesis, and many antibiotics have been developed to target the transpeptidase; however, the problem of antibiotic resistance has arisen and caused a major threat in bacterial infection. The transglycosylase has been considered to be another excellent target, but no antibiotics have been developed to target this enzyme. Here, we determined the crystal structure of the Staphylococcus aureus membrane-bound transglycosylase, monofunctional glycosyltransferase, in complex with a lipid II analog to 2.3 Å resolution. Our results showed that the lipid II-contacting residues are not only conserved in WT and drug-resistant bacteria but also significant in enzymatic activity. Mechanistically, we proposed that K140 and R148 in the donor site, instead of the previously proposed E156, are used to stabilize the pyrophosphate-leaving group of lipid II, and E100 in the acceptor site acts as general base for the 4-OH of GlcNAc to facilitate the transglycosylation reaction. This mechanism, further supported by mutagenesis study and the structure of monofunctional glycosyltransferase in complex with moenomycin in the donor site, provides a direction for antibacterial drugs design.