Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey; Department of Biology, Amasya University, 05100 Amasya, Turkey.
Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey.
Biochem Pharmacol. 2017 Jun 1;133:43-62. doi: 10.1016/j.bcp.2016.10.005. Epub 2016 Oct 17.
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.
青霉素的发现，随后是链霉素、四环素、头孢菌素和其他天然、半合成和合成的抗菌药物，通过降低大多数常见感染导致的人类发病率和死亡率，彻底改变了医学。然而，在它们被引入临床实践后不久，就出现了耐药性的问题。尽管抗生素耐药性在全球迅速出现，但抗生素产业的兴趣却在下降，这从公共卫生的角度来看是一个严峻的困境。抗菌药物治疗的效果取决于药代动力学和药效动力学。尽管抗生素具有选择性毒性，但由于药物代谢缺陷或剂量方案过大，它们仍会在宿主体内引起严重的、危及生命的不良反应。本文旨在更新关于药代动力学/药效动力学概念和模型、抗生素毒性以及抗生素耐药机制、耐药组分析和寻找新型抗生素耐药决定因素的最新知识，特别强调多药外排泵的最新进展及其在细菌应激适应和毒力方面的其他生理功能。所有这些问题都密切相关，不仅对当前抗生素的最有效和最长时间使用非常重要，而且对新抗生素和病原体抗生素耐药决定因素的新型抑制剂的发现和开发也非常重要。
