Zgurskaya Helen I, Rybenkov Valentin V, Krishnamoorthy Ganesh, Leus Inga V
Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.
Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.
Res Microbiol. 2018 Sep-Oct;169(7-8):351-356. doi: 10.1016/j.resmic.2018.02.002. Epub 2018 Feb 16.
Antibiotic resistance is a serious threat to public health. Significant efforts are currently directed toward containment of the spread of resistance, finding new therapeutic options concerning resistant human and animal pathogens, and addressing the gaps in the fundamental understanding of mechanisms of resistance. Experimental data and kinetic modeling revealed a major factor in resistance, the synergy between active efflux and the low permeability barrier of the outer membrane, which dramatically reduces the intracellular accumulation of many antibiotics. The structural and mechanistic particularities of trans-envelope efflux pumps amplify the effectiveness of cell envelopes as permeability barriers. An important feature of this synergism is that efflux pumps and the outer membrane barriers are mechanistically independent and select antibiotics based on different physicochemical properties. The synergism amplifies even weak polyspecificity of multidrug efflux pumps and creates a major hurdle in the discovery and development of new therapeutics against Gram-negative pathogens.
抗生素耐药性是对公众健康的严重威胁。目前正投入大量努力来遏制耐药性的传播，寻找针对耐药的人类和动物病原体的新治疗选择，并填补对耐药机制基本理解方面的空白。实验数据和动力学模型揭示了耐药性的一个主要因素，即主动外排与外膜低通透性屏障之间的协同作用，这极大地减少了许多抗生素在细胞内的积累。跨膜外排泵的结构和机制特性增强了细胞膜作为通透性屏障的有效性。这种协同作用的一个重要特征是外排泵和外膜屏障在机制上是独立的，并根据不同的物理化学性质选择抗生素。这种协同作用放大了多药外排泵即使很弱的多特异性，并在针对革兰氏阴性病原体的新疗法的发现和开发中造成了一个主要障碍。
