Klopman G, Wang S, Jacobs M R, Ellner J J
Chemistry Department, Case Western Reserve University, Cleveland, Ohio 44106.
Antimicrob Agents Chemother. 1993 Sep;37(9):1807-15. doi: 10.1128/AAC.37.9.1807.
The structures and inhibitory activities of 88 quinolones, previously studied as potential in vitro inhibitors of 14 selected strains of Mycobacterium avium complex, were examined in an effort to identify a quinolone with optimal activity towards all strains. A MULTICASE structure-activity relationship analysis of the inhibitory activities of these 88 quinolones against 14 strains of M. avium was performed and led to the identification of a number of structural constraints required to overcome the resistance of most of the strains. Our data suggested that the increased resistance of the strains was probably not due to a specific resistance mechanism but rather due to gradual limitation of the constraints imposed on the structure of the quinolones. This increasing structural selectivity could be produced either at the level of cell membrane penetration or at the level of interaction with the DNA gyrase receptor site. On the basis of these findings, a number of new quinolones holding the promise of superior activity are currently being evaluated in vitro and in vivo to determine the clinical relevance of our observations.
曾作为14株鸟分枝杆菌复合体潜在体外抑制剂进行研究的88种喹诺酮类药物的结构和抑制活性，经过检测以确定一种对所有菌株均具有最佳活性的喹诺酮类药物。对这88种喹诺酮类药物针对14株鸟分枝杆菌的抑制活性进行了多病例构效关系分析，结果确定了克服大多数菌株耐药性所需的一些结构限制因素。我们的数据表明，菌株耐药性增加可能并非由于特定的耐药机制，而是由于对喹诺酮类药物结构所施加限制的逐渐受限。这种结构选择性的增加可能在细胞膜渗透水平或与DNA回旋酶受体位点相互作用的水平产生。基于这些发现，目前正在体外和体内评估一些有望具有更高活性的新型喹诺酮类药物，以确定我们观察结果的临床相关性。
