Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa.
Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa.
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DOI：
10.3402/ljm.v6i0.5870
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发表时间：
2011-05-13
期刊：
影响因子：
--
通讯作者：
Taher I
中科院分区：
文献类型：
--
作者：
Askoura M;Mottawea W;Abujamel T;Taher I
铜绿假单胞菌是一种机会性人类病原体，也是世界范围内医院感染的主要原因之一。假单胞菌感染的治疗困难来自于多药耐药（MDR），并且由于克服其作用的不同机制的表达而对大多数抗菌药物表现出耐药性。在这些耐药机制中，铜绿假单胞菌属耐药结瘤分裂（RND）的主动外排泵在将抗生素挤出细菌细胞外的过程中起着非常重要的作用，为抵抗细菌的抗菌活性提供了保护手段。除了它的作用对抗抗菌剂，这些泵可以挤出杀菌剂，洗涤剂，和其他代谢抑制剂。很明显，外排泵可以成为新的抗菌药物的靶点。类肽化合物如苯丙氨酸精氨酸β-萘酰胺（PAβN）已被引入作为外排泵抑制剂（EPIs）；其作用机制是通过与抗生素竞争抑制外排泵，导致细胞内抗生素浓度增加，从而恢复其抗菌活性。EPIs的优点是细菌对其难以产生耐药性，缺点是其毒性阻碍了其临床应用。这些化合物的构效关系表明，PAβN的其他衍生物活性更高，在生物体液中的溶解度更高，毒性水平更低。这进一步提出了如何压缩假单胞菌感染的问题。特别重要的是，最近重新使用多粘菌素等较旧抗生素，并可能采取更严格的控制措施，以防止其在临床场所传播。
Pseudomonas aeruginosa is an opportunistic human pathogen and one of the leading causes of nosocomial infections worldwide. The difficulty in treatment of pseudomonas infections arises from being multidrug resistant (MDR) and exhibits resistance to most antimicrobial agents due to the expression of different mechanisms overcoming their effects. Of these resistance mechanisms, the active efflux pumps in Pseudomonas aeruginosa that belong to the resistance nodulation division (RND) plays a very important role in extruding the antibiotics outside the bacterial cells providing a protective means against their antibacterial activity. Beside its role against the antimicrobial agents, these pumps can extrude biocides, detergents, and other metabolic inhibitors. It is clear that efflux pumps can be targets for new antimicrobial agents. Peptidomimetic compounds such as phenylalanine arginyl β-naphthylamide (PAβN) have been introduced as efflux pump inhibitors (EPIs); their mechanism of action is through competitive inhibition with antibiotics on the efflux pump resulting in increased intracellular concentration of antibiotic, hence, restoring its antibacterial activity. The advantage of EPIs is the difficulty to develop bacterial resistance against them, but the disadvantage is their toxic property hindering their clinical application. The structure activity relationship of these compounds showed other derivatives from PAβN that are higher in their activity with higher solubility in biological fluids and decreased toxicity level. This raises further questions on how can we compact Pseudomonas infections. Of particular importance, the recent resurgence in the use of older antibiotics such as polymyxins and probably applying stricter control measures in order to prevent their spread in clinical sittings.
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