Braun Volkmar
Mikrobiologie/Membranphysiologie, Universität Tübingen, Auf der Morgenstelle 28, Tübingen, D-72076, Germany
Drug Resist Updat. 1999 Dec;2(6):363-369. doi: 10.1054/drup.1999.0107.
The outer membrane of gram-negative bacteria forms a permeability barrier that usually reduces antibiotic access to intracellular targets and renders gram-negative bacteria less susceptible to antibiotics than gram-positive bacteria, which lack an outer membrane. However, gram-negative bacteria become highly susceptible to antibiotics that are actively transported across the outer membrane. Some antibiotics use active transport systems of substrates with which they share structural features. Examples are naturally occurring sideromycins and synthetic derivatives of Fe(3+)-siderophores, which are taken up across the outer membrane by transport systems for Fe(3+)-siderophores. A well-studied example is albomycin, which has structural similarities to the natural substrate ferrichrome; albomycin and ferrichrome are both transported by the FhuA protein. A semisynthetic rifamycin derivative, CGP 4832, is also taken up by the FhuA transport protein, although its structure is completely different from that of ferrichrome. The crystal structures of FhuA with bound ferrichrome, albomycin, or rifamycin CGP 4832 reveal that the three compounds occupy the same site on FhuA; this site is accessible from the growth medium by a surface cavity that accommodates the antibiotic moieties. There is a rather strict stereochemical requirement for the portion that fits into the active site of FhuA, but a rather large tolerance regarding the portion that is located in the cavity. These data provide precise structural information for the design of highly active antibiotics composed of an antibiotically active moiety connected by a linker to a transported carrier. A number of Fe(3+)-siderophore carriers of the hydroxamate and catechol type linked to antibiotics have been isolated from microbes and synthesized; their superior efficacy has been demonstrated in vitro and in mice. Although none have been therapeutically employed, it is proposed that this alternative method of synthesizing useful antibiotics should be tested in light of the increasing problem of resistant pathogens. Copyright 1999 Harcourt Publishers Ltd.
革兰氏阴性菌的外膜形成了一道渗透屏障，通常会减少抗生素与细胞内靶点的接触，使得革兰氏阴性菌比缺乏外膜的革兰氏阳性菌对抗生素更不敏感。然而，革兰氏阴性菌对那些能被主动转运穿过外膜的抗生素高度敏感。一些抗生素利用与它们具有结构相似性的底物的主动转运系统。例子包括天然存在的铁霉素和Fe(3+) - 铁载体的合成衍生物，它们通过Fe(3+) - 铁载体的转运系统穿过外膜。一个经过充分研究的例子是白霉素，它与天然底物铁色素具有结构相似性；白霉素和铁色素都由FhuA蛋白转运。一种半合成利福霉素衍生物CGP 4832也被FhuA转运蛋白摄取，尽管其结构与铁色素完全不同。结合了铁色素、白霉素或利福霉素CGP 4832的FhuA的晶体结构表明，这三种化合物占据FhuA上的同一个位点；这个位点可通过容纳抗生素部分的表面腔从生长培养基进入。对于适合FhuA活性位点的部分有相当严格的立体化学要求，但对于位于腔内的部分则有相当大的耐受性。这些数据为设计由通过连接子连接到转运载体的抗生素活性部分组成的高活性抗生素提供了精确的结构信息。已经从微生物中分离并合成了许多与抗生素相连的异羟肟酸和儿茶酚类型的Fe(3+) - 铁载体；它们在体外和小鼠体内都显示出了卓越的疗效。尽管尚未有用于治疗的情况，但鉴于耐药病原体问题日益严重，有人提议应该对这种合成有用抗生素的替代方法进行测试。版权所有1999年哈考特出版有限公司
