據(jù)臺(tái)灣《聯(lián)合晚報(bào)》報(bào)道,，臺(tái)灣“中央研究院”院長(zhǎng)翁啟惠和基因體研究中心副研究員馬徹共同領(lǐng)導(dǎo)的研究團(tuán)隊(duì)，成功解構(gòu)了細(xì)菌的保護(hù)屏障,，突破了苦惱全球科學(xué)家20年的“細(xì)菌謎團(tuán)”,。
長(zhǎng)久以來(lái)，醫(yī)藥界一直以轉(zhuǎn)勝肽酶為標(biāo)的,，設(shè)計(jì)出一系列對(duì)抗細(xì)菌的抗生素,，其中最有名的就是盤(pán)尼西林；然而,，隨著細(xì)菌抗藥性的增加,，這類(lèi)抗生素的威力大不如前，人類(lèi)在遭受各種細(xì)菌的強(qiáng)大威脅時(shí),，也逐漸面臨無(wú)藥可用的窘境,。
馬徹說(shuō)，雖然科學(xué)家清楚知道透過(guò)抑制轉(zhuǎn)醣酶來(lái)開(kāi)發(fā)新一代抗生素,，但因?qū)D(zhuǎn)醣酶的結(jié)構(gòu)及作用機(jī)制不清楚,，20年來(lái)進(jìn)展有限,。“中研院”基因體研究中心近年來(lái)針對(duì)轉(zhuǎn)醣酶進(jìn)行一系列研究，成功利用X光繞射方法,，清晰解構(gòu)出金黃色葡萄球菌細(xì)胞壁上轉(zhuǎn)醣酶及其受質(zhì)的復(fù)合結(jié)構(gòu),。今后只要設(shè)計(jì)出可阻斷轉(zhuǎn)醣酶繼續(xù)作用下去的小分子藥物，就能開(kāi)發(fā)出可殺死細(xì)菌的新一代抗生素,。
據(jù)報(bào)道,，這項(xiàng)重要的研究發(fā)現(xiàn)，發(fā)表在“美國(guó)國(guó)家科學(xué)院期刊”最新一期刊物中,，引起全球科學(xué)界高度重視,。翁啟惠認(rèn)為，這是未來(lái)解決具抗藥性細(xì)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.
