Striving to understand the molecular details of a basic and most important process of life, namely the translation of the genetic code, we determined the structure of the ribosome, the universal cellular "factory" that performed the formation of the proteins (the cell workers) according to the genetic code. We further determined the structures of ribosomal particles in complex with its substrates, inhibitors and various molecular factors that interact with it. Based on these structural tools we deciphered the ribosome's mode of function and the way antibiotics can paralyze it. Thus, owing to its vital role in cell life, the ribosome is targeted by many antibiotics, which hamper the ribosomes function by binding to their functional sites. Consequently the antibiotics binding modes, inhibitory actions and synergism pathways have been determined for almost all ribosomal antibiotics. These indicated the principles of differentiation between patients and pathogens, suggested mechanisms leading to bacterial resistance and paved ways for improvement of existing antibiotics as well as for the design of advanced therapeutics capable of minimizing antibiotics resistance. Furthermore, as resistance to antibiotics was found to be species specific, we have determined the first and only structure of a ribosome from a multi-resistant bacterium and discovered that even the minute variability between the pathogens and their non-pathogenic eubacterial models, result in tiny, albeit meaningful differences that may be used for the design of specific antibiotics, namely sort-of bacterial "personalized medicine".

核醣體是所有細胞的「工廠」，能夠將遺傳密碼轉譯成蛋白質，成為細胞功能的執行者。基因密碼的轉譯，因而成為生命最基本也極其重要的步驟，勃然誘發我們對其過程的好奇心。為了要瞭解其分子機制，我們針對核醣體的結構進行分析，並進一步分析核醣體和其受質、抑制物、以及不同分子間作用所形成的複合體結構，深入探討其中奧秘。 由於核醣體在細胞存活中扮演重要角色，因而成為許多抗生素藥物的作用標的。換言之，抗生素透過與微生物內核醣體的功能位結合，可抑制其功能而得到滅菌效果。基於上述對核醣體結構的研究，我們成功破解出病原菌核醣體作用的方式，以及其被抗生素抑制的途徑。此外，大多數針對病原菌核醣體的抗生素，其結合方式、抑制作用以及協同途徑，也都被詳加分析。這些研究成果讓我們知道該如何區分受感染病患的細胞與病原菌、解釋細菌產生抗藥性的機制，並且為提升現有抗生素功能，以及該如何設計出新一代抗生素作出貢獻。 由於微生物的抗生素耐藥性大多具有物種專一性，因此我們也針對一個具多重抗藥性細菌的核醣體進行深入的分析。我們發現，即使在致病性及其非致病性真細菌之間構型僅有些少許變異，仍會造成微妙但具特殊意義的差別，而此差別或可用於設計具專一性的抗生素，也就是類似針對特定細菌感染有特別療效的「個人化藥物」。 （感謝清華大學醫學科學系莊永仁教授協助翻譯）