Biochemistry of Bacterial Cell Membranes

病原菌中多重耐药性的增加是对人类的一大威胁 健康。尤其是革兰氏阴性细菌往往对多种抗菌剂具有内在抗药性。 这种固有的耐药性很容易通过常见的突变而增加。在我们的研究中 以及最近几年的其他实验室得出的结论是，这种耐药性经常是由 阻止药剂接触细菌细胞内目标的机制。两个“障碍”在一个 真正的协同方式。首先，革兰氏阴性外膜极大地阻碍了抗菌剂的进入 亲水性和亲脂性的试剂，因为孔蛋白通道的狭窄或稀少使进入 对亲水性试剂的研究很困难，而且因为脂多糖-磷脂的不对称双层 膜极大地减缓了亲脂剂的进入。第二，几个抗生素分子 成功通过外膜被无处不在的多药外排泵主动泵出 通常表现出令人难以置信的广泛的底物专一性。在多种药物中泵经常被过度生产- 来自临床来源的耐药菌株；这种机制特别麻烦，因为使用单一的 药物可导致对大多数现有抗生素同时产生抗药性。我们将继续研究这两个问题 访问防止机制的各个阶段。在外膜通透性方面，我们将研究 一些孔蛋白被折叠，只产生几个开放的通道的机制。我们亦会研究 内毒素-磷脂双层膜异常形成的分子机制 不透性，并将首次测量氨基糖苷类药物穿过外膜的进入情况。 在多药外排泵领域，我们将继续研究主要的 大肠杆菌的多药外排泵，AcrAB-TolC，以了解为什么这种转运体可以处理这样的 各种各样的化合物。这些研究结果将对人工合成技术的发展具有重要的参考价值。 以及未来的半合成抗菌化合物。

The increasing prevalence of multiple drug resistance in pathogenic bacteria is a major threat to human health. Especially Gram-negative bacteria are often intrinsically resistant to a number of antimicrobial agents, and such intrinsic resistance may easily become increased by common mutations. Studies in our and other laboratories in recent years led to the conclusion that such resistance is frequently mediated by mechanisms preventing the access of agents to their targets inside bacterial cells. Two "barriers" work in a truly synergistic manner. First, the Gram-negative outer membrane greatly retards the entry of antimicrobial agents, both hydrophilic and lipophilic, because the narrowness or paucity of porin channels makes the entry of hydrophilic agents difficult, and because the lipopolysaccharide-phospholipid asymmetric bilayer of this membrane slows down drastically the entry of lipophilic agents. Second, a few molecules of antibiotics that succeed in crossing the outer membrane are actively pumped out by ubiquitous multidrug efflux pumps that often show an incredibly wide substrate specificity. The pumps are frequently overproduced in the multidrug- resistant strains from clinical sources; this mechanism is especially troublesome because the use of a single drug can lead to simultaneous resistance to most of the existing antibiotics. We will continue to study both phases of the access-prevention mechanism. In the area of outer membrane permeability, we will study the mechanism whereby some porins are folded to produce only a few open channels. We will also study the molecular mechanism which makes the lipopolysaccharide-phospholipid bilayer so exceptionally impermeable, and will measure, for the first time, the entry of aminoglycosides across the outer membrane. In the area of multidrug efflux pumps, we will continue our studies of the structure and function of the major multidrug efflux pump of Escherichia coli, AcrAB-TolC, to understand why this transporter can handle such a wide range of compounds. The results of these studies will be very useful for the development of synthetic and semisynthetic antimicrobial compounds in the future.