Mettalloenzyme Structure/Function

这项研究的长期目标是在分子水平上了解β-内酰胺酶的催化机制和抑制作用，并通过这种了解促进小分子疗法的发展。细菌对β-内酰胺类抗生素的耐药性在过去十年中已成为一个主要的健康问题。β-内酰胺类抗生素通过阻止细菌细胞壁的完全合成而杀死细菌，从而导致有缺陷的细胞壁，细胞壁在细胞的高内部压力下破裂。细菌通过三种主要方式制定了抗生素耐药性策略：产生被称为β-内酰胺酶的水解酶，改变细胞膜的通透性，以及改变目标酶。在这些机制中，由自然选择无情地推动的β-内酰胺酶的产生，通常被认为是对β-内酰胺类抗生素产生耐药的主要途径。值得注意的是，这些酶可以是染色体或质粒编码的，并被革兰氏阴性菌分泌到周质空间或由革兰氏阳性菌分泌到外部介质中，从而促进了对β-内酰胺类抗生素的耐药性传播。由于不断需要发现新的抗生素，抗β-内酰胺类药物的出现也产生了巨大的社会和经济影响。将用于实现长期目标的工具包括理论化学、药物化学和生物化学。将研究的主要酶是蜡状芽孢杆菌和脆弱芽孢杆菌的β-内酰胺酶。借助这些工具，将研究β-内酰胺酶-底物相互作用、β-内酰胺酶-抑制剂相互作用和由这些β-内酰胺酶催化的反应的性质和能量学。对这些过程的洞察将对人类健康产生重大影响，因为它将促进新药的设计，这些新药将消除至少一种抗β-内酰胺活性的细菌机制，这反过来又将延长现有抗生素的寿命。

The long-term goal of this research is to understand, at the molecular level, the catalytic mechanism and inhibition of beta-lactamases and through this understanding facilitate the development of small-molecule therapeutics. Bacterial resistance to beta-lactam antibiotics has emerged over the past decade as a major health concern. Beta-lactam antibiotics kill bacteria by preventing the complete synthesis of the bacterial cell wall leading to a defective cell wall, which ruptures under the high internal pressure of the cell. Bacteria have developed antibiotic- resistance strategies in three major ways: production of hydrolytic enzymes known as beta-lactamases, changes in the permeability of the cell membrane, and alterations of the target enzymes. Among these mechanisms, beta-lactamase production, relentlessly fueled by natural selection, is generally considered as the primary route of resistance to beta-lactam antibiotics. Significantly, these enzymes can be chromosome or plasmid encoded and are secreted into the periplasmic space of Gram- negative bacteria or into the outer medium by Gram-positive bacteria, which facilitates the spread of beta-lactam resistance. The emerg3ence of anti-beta-lactam activity also has a tremendous social and financial impact because of the continuous need to discover novel antibiotics. The tools that will be used to reach the long-term goal are those of theoretical chemistry, medicinal chemistry and biochemistry. The primary enzymes that will be studied are the beta-lactamases from B. cereus and B. Fragilis. With the aid of these tools the nature and energetics of beta-lactamase-substrate interactions, beta-lactamase- inhibitor interactions and reactions catalyzed by these beta-lactamases will be examined. The insights obtained into these processes will have a major impact on human health by facilitating the design of new drugs that will eliminate at least one bacterial mechanism for anti-beta-lactam activity, which will in turn increase the lifetime of existing antibiotics.