Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Curr Med Chem. 2018;25(42):6030-6069. doi: 10.2174/0929867325666180209142612.
Antibiotic resistance is one of the most pressing health issues of our days. It can arise due to a multiplicity of factors, such as target modification, decrease in the drug uptake, changes in the metabolic pathways and activation of efflux pumps. The overexpression of efflux pumps is responsible for the extrusion of drugs, making antibiotic therapy fail, as the quantity of intracellular antibiotic is not enough to provide the desired therapeutic effect. Efflux pumps can be included in five families according to their composition, nature of substrates, energy source, and number of transmembrane spanning regions. The ABC superfamily is mainly found in Gram-positive bacteria, use ATP as an energy source, and only a limited number of ABC pumps confer multidrug resistance (MDR). On the other hand, the MFS family, most present in Gram-positive bacteria, and the RND family, characteristic of Gram-negative bacteria, are most associated with antibiotic resistance. A wide variety of inhibitors have been disclosed for both families, from either natural or synthetic sources, or even drugs that are currently in therapy for other diseases. The other two families are the SMR, which are the smallest drug efflux proteins known, and the MATE family, whose pumps can also resort to the sodium gradient as an energy source. In this review, it is intended to present a comprehensive review of the classes of efflux pump inhibitors from the various sources, highlighting their structure-activity relationships, which can be useful for medicinal chemists in the pursuit of novel efflux pump inhibitors.
抗生素耐药性是当今最紧迫的健康问题之一。它可能由于多种因素引起，例如靶标修饰、药物摄取减少、代谢途径改变和外排泵激活。外排泵的过度表达负责将药物排出，使抗生素治疗失败，因为细胞内抗生素的数量不足以产生所需的治疗效果。根据组成、底物性质、能量来源和跨膜区数量，外排泵可分为五类。ABC 超家族主要存在于革兰氏阳性菌中，使用 ATP 作为能量来源，只有少数 ABC 泵赋予多药耐药性（MDR）。另一方面，MFS 家族，主要存在于革兰氏阳性菌中，以及 RND 家族，革兰氏阴性菌的特征，与抗生素耐药性最相关。已经从天然或合成来源，甚至从目前用于治疗其他疾病的药物中，发现了大量针对这两个家族的抑制剂。另外两个家族是 SMR，它是已知的最小的药物外排蛋白，而 MATE 家族的泵也可以利用钠离子梯度作为能量来源。在这篇综述中，旨在从各种来源全面介绍外排泵抑制剂的类别，突出其结构-活性关系，这对药物化学家在寻找新型外排泵抑制剂方面可能是有用的。
