Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada N2L 3G1.
J Am Chem Soc. 2010 Mar 3;132(8):2558-60. doi: 10.1021/ja9086374.
The most important mode of bacterial resistance to beta-lactam antibiotics is the expression of beta-lactamases. New cyclobutanone analogues of penams and penems have been prepared and evaluated for inhibition of class A, B, C, and D beta-lactamases. Inhibitors which favor conformations in which the C4 carboxylate is equatorial were found to be more potent than those in which the carboxylate is axial, and molecular modeling studies with enzyme-inhibitor complexes indicate that an equatorial orientation of the carboxylate is required for binding to beta-lactamases. An X-ray structure of OXA-10 complexed with a cyclobutanone confirms that a serine hemiketal is formed in the active site and that the inhibitor adopts the exo envelope. An unsaturated penem analogue was also found to enhance the potency of meropenem against carbapenem-resistant MBL-producing strains of Chryseobacterium meningosepticum and Stenotrophomonas maltophilia. These cyclobutanones represent the first type of reversible inhibitors to show moderate (low micromolar) inhibition of both serine- and metallo-beta-lactamases and should be considered for further development into practical inhibitors.
细菌对β-内酰胺类抗生素产生耐药性的最重要方式是β-内酰胺酶的表达。我们已经制备了新型的环丁酮青霉烷类和青霉烯类化合物，并对其抑制 A、B、C 和 D 类β-内酰胺酶的活性进行了评估。研究发现，有利于 C4 羧酸处于平伏键位置的抑制剂比羧酸处于直立键位置的抑制剂的活性更强，并且通过与酶-抑制剂复合物的分子建模研究表明，羧酸的平面取向是与β-内酰胺酶结合所必需的。与 OXA-10 形成复合物的环丁酮的 X 射线结构证实，在活性部位形成了丝氨酸半缩酮，并且抑制剂采用了反式 envelope 构象。还发现一种不饱和的青霉烯类似物可增强美罗培南对脑膜炎败血性黄杆菌和嗜麦芽窄食单胞菌产生的碳青霉烯酶耐药株的活性。这些环丁酮类化合物是首次显示对丝氨酸和金属β-内酰胺酶具有中等（低微摩尔）抑制作用的可逆抑制剂，应考虑进一步开发为实用的抑制剂。
