Zwama Martijn, Nishino Kunihiko
SANKEN (The Institute of Scientific and Industrial Research), Osaka University, Ibaraki, Osaka 567-0047, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
Antibiotics (Basel). 2021 Jun 25;10(7):774. doi: 10.3390/antibiotics10070774.
The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR is the over-expression of intrinsic and acquired multidrug efflux pumps, belonging to the resistance-nodulation-division (RND) superfamily, which can efflux a wide range of structurally different antibiotics. Besides over-expression, however, recent amino acid substitutions within the pumps themselves-causing an increased drug efflux efficiency-are causing additional worry. In this review, we take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from , , , , and ). We also focus on the evolution of the efflux pumps by comparing hundreds of efflux pumps to determine where conservation is concentrated and where differences in amino acids can shed light on the broad and even broadening drug recognition. Knowledge of conservation, as well as of novel gain-of-function efflux pump mutations, is essential for the development of novel antibiotics and efflux pump inhibitors.
多重耐药性（MDR）的增加是全球人类健康面临的最大威胁之一。细菌病原体中的多重耐药性是医疗保健领域的一项重大挑战，因为细菌感染正变得无法用市售抗生素治疗。多重耐药性的主要原因之一是属于耐药-固氮-细胞分裂（RND）超家族的内在和获得性多药外排泵的过度表达，这些泵可以外排多种结构不同的抗生素。然而，除了过度表达之外，泵本身最近发生的氨基酸替代——导致药物外排效率提高——也引发了更多担忧。在这篇综述中，我们仔细研究了临床、环境和实验室进化的革兰氏阴性细菌菌株，以及由于RND型泵本身直接发生突变（来自 、 、 、 和 ）而导致的药物敏感性降低。我们还通过比较数百种外排泵来关注外排泵的进化，以确定保守性集中在哪里，以及氨基酸差异在哪里可以揭示广泛甚至不断扩大的药物识别。了解保守性以及新型功能获得性外排泵突变对于新型抗生素和外排泵抑制剂的开发至关重要。
