摘要
      青霉素以及链霉素、四环素、头孢菌素和其他天然、半合成和合成抗菌剂的发现彻底改变了医学，降低了人类大多数常见感染的发病率和死亡率。然而，在他们被引入临床实践后不久，抗药性也随之发展。尽管全球范围内抗生素耐药性迅速出现，抗生素产业的兴趣却在下降，从公共卫生的角度来看，这是一个艰难的困境。抗菌药物的疗效由药动学和药效学决定。虽然抗生素具有选择性毒性，但主要由于药物代谢缺陷或过量给药方案，抗生素仍会在宿主体内引起严重的，危及生命的不良反应。本文旨在更新药物动力学/药效学的概念和模型、抗生素的毒性以及抗生素耐药机制、耐药性分析和寻找新的抗生素耐药决定因素，重点介绍多药外排泵及其在应激适应和细菌毒力中的附加生理功能的研究进展。所有这些问题都是高度相关的，不仅对当前抗生素的最高效使用和长期使用非常重要，而且对发现和开发新的抗生素和病原体抗生素耐药决定簇的新型抑制剂也非常重要。


      The discovery of penicillin followed by streptomycin, tetracycline, cephalosporins and other natural, semi-synthetic and synthetic antimicrobials completely revolutionized medicine by reducing human morbidity and mortality from most of the common infections. However, shortly after they were introduced to clinical practice, the development of resistance was emerged. The decreasing interest from antibiotic industry in spite of rapid global emergence of antibiotic resistance is a tough dilemma from the pointview of public health. The efficiency of antimicrobial treatment is determined by both pharmacokinetics and pharmacodynamics. In spite of their selective toxicity, antibiotics still cause severe, life-threatening adverse reactions in host body mostly due to defective drug metabolism or excessive dosing regimen. The present article aims at updating current knowledge on pharmacokinetics/pharmacodynamics concepts and models, toxicity of antibiotics as well as antibiotic resistance mechanisms, resistome analyses and search for novel antibiotic resistance determinants with special emphasis given to the-state-of-the-art regarding multidrug efflux pumps and their additional physiological functions in stress adaptation and virulence of bacteria. All these issues are highly linked to each other and not only important for most efficient and prolonged use of current antibiotics, but also for discovery and development of new antibiotics and novel inhibitors of antibiotic resistance determinants of pathogens.

https://www.sciencedirect.com/science/article/abs/pii/S0006295216303513