| Summary: | 碩士 === 國立中正大學 === 化學研究所 === 90 === Human uses medicine to fight and defeat bacteria; bacteria, consequently, employ drug resistance to defend and survive. Understanding the mechanisms involved in bacterial drug resistance and, thereafter, developing the mechanism-based antimicrobial agents are keys to prevail over bacteria. To effectively design new agents to combat bacterial drug resistance, it is important to consider the so-called selective toxicity; that is to say, the detailed understanding of the fundamental molecular differences between human and bacterial cells plays a critical role. This explains that many popular antibiotics, including penicillins, act on bacterial cell walls, which are lacking in human cells. As to the bacterial drug resistance mechanism known today, four different mechanisms are often employed by bacteria: (i) the prevention of intracellular medicine accumulation, (ii) the alteration in the target of the medicine, (iii) the production of enzyme(s) that efficiently inactivates medicine, and (iv) the generation of a specific metabolism route in which it cannot be inhibited by the medicine.
In this thesis, we first stressed the epidemic of bacterial drug resistance today and summarized its up-to-date molecular mechanisms involved. Vancomycin-resistant enterococci (VRE) was then our focus and used to comprehensively describe the chemistry and biology of the VRE-specific proteins (VanS, VanR, VanA, VanH and VanX). It is concluded that VanS and VanR are responsible for the sensing and the signal transduction of the antibiotic, vancomycin; VanA is a D-Ala-D-Lactate ligase; VanH is the D-hydroxy acid dehydrogenase, and VanX is the D-Ala-D-Ala dipeptidase. Lastly, we explored how these proteins work as a team to ingeniously modify the bacterial cell walls that eventually resist vancomycin.
We extensively studied the VanX protein in this work for the reason that it shows no homology with all mammalian proteins. Using site-directed mutagenesis, the active site of VanX was revealed and its mechanism of action has been proposed. Although several mechanism-based inhibitors have been reported, they however were marginally effective. The development of more effective VanX inhibitors is desperately needed.
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