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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Design, synthesis and microbiological evaluation of ampicillin-tetramic acid hybrid antibiotics
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Design, synthesis and microbiological evaluation of ampicillin-tetramic acid hybrid antibiotics

机译：氨苄青霉素 - 四酸杂交抗生素的设计，合成和微生物评估

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Exploiting iron-uptake pathways by conjugating (beta-lactam antibiotics with iron-chelators, such as catechol and hydroxamic acid is a proven strategy to overcome permeability-related resistance in Gram-negative bacteria. As naturally occurring iron-chelating tetramic acids have not been previously examined for this purpose, an exploratory series of novel ampicillin-tetramic acid hybrids that structurally resemble ureidopenicillins was designed and synthesized. The new analogs were evaluated for the ability to chelate iron and their MIC activities determined against a representative panel of clinically significant bacterial pathogens. The tetramic acid beta-lactam hybrids demonstrated a high affinity to iron in the order of 10(-30) M-3. The hybrids were less active against Gram-positive bacteria. However, against Gram-negative bacteria, their activity was species dependent with several hybrids displaying improved activity over ampicillin against wild-type Pseudomonas aeruginosa. The anti-Gram-negative activities of the hybrids improved in the presence of clavulanic acid revealing that the tetramic acid moiety did not provide added protection against beta-lactamases. In addition, the hybrids were found to be efflux pump substrates as their activities markedly improved against pump-inactivated strains. Unlike the catechol and hydroxamic acid siderophore beta-lactam conjugates, the activities of the hybrids did not improve under iron-deficient conditions. These results suggest that the tetramic acid hybrids gain permeability via different membrane receptors, or they are outcompeted by native bacterial siderophores with stronger affinities for iron. This study provides a foundation for the further exploitation of the tetramic acid moiety to achieve novel beta-lactam anti-Gram-negative agents, providing that efflux and beta-lactamase mediated resistance is addressed.
机译：通过缀合（β-内酰胺抗生素与铁螯合剂等CateChol和羟肟酸等耐烧制途径是克服革兰氏阴性细菌中渗透性相关性的经过验证的策略。由于天然存在的铁螯合的四酸，并未出现以前检查了该目的，设计和合成了一种结构类似于ureidopenicillins的新型氨苄青霉素 - 四酸杂种的探索性系列。评估了螯合铁的能力及其针对临床显着的细菌病原体代表小组确定的新类似物的能力。四酸β-内酰胺杂种杂交物以10（-30）m-3的约束对铁具有高亲和力。杂种对革兰氏阳性细菌的活性较小。然而，针对革兰氏阴性细菌，它们的活性是物种依赖于几种杂种，在野生型假单胞菌铜绿假单胞菌上显示出改善的Ampicillin活性。该杂交种的Ti-gram阴性活性在克拉维酸的存在下改善了克拉维酸的存在，揭示了四酸部分没有提供对β-内酰胺酶的添加保护。此外，发现杂交种是流出泵衬底，因为它们的活性显着改善泵灭绝的菌株。与儿茶酚和异羟肟酸β-内酰胺缀合物不同，杂交种的活性在铁缺陷条件下没有改善。这些结果表明，四酸杂交物通过不同的膜受体产生渗透性，或者它们是由天然细菌施用的耐受性具有更强的铁的耐受性。本研究为进一步开采四硫酸部分以实现新的β-内酰胺抗革兰阴性剂，提供了一种基础，提供了所介绍渗透和β-内酰胺酶介导的抗性。

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