Organic Chemistry Section, Department of Inorganic and Organic Chemistry, Faculty of Chemistry, University of Barcelona, Spain.
Nat Prod Rep. 2017 Jul 6;34(7):886-908. doi: 10.1039/c7np00023e.
Covering: 1947-early 2017, particularly from 2005-early 2017The rise of bacterial pathogens with acquired resistance to almost all available antibiotics is becoming a serious public health issue. Polymyxins, antibiotics that were mostly abandoned a few decades ago because of toxicity concerns, are ultimately considered as a last-line therapy to treat infections caused by multi-drug resistant Gram-negative bacteria. This review surveys the progress in understanding polymyxin structure, and their chemistry, mechanisms of antibacterial activity and nephrotoxicity, biomarkers, synergy and combination with other antimicrobial agents and antibiofilm properties. An update of recent efforts in the design and development of a new generation of polymyxin drugs is also discussed. A novel approach considering the modification of the scaffold of polymyxins to integrate metabolism and detoxification issues into the drug design process is a promising new line to potentially prevent accumulation in the kidneys and reduce nephrotoxicity.
1947 年至 2017 年初，特别是 2005 年至 2017 年初 具有几乎所有现有抗生素获得性耐药性的细菌病原体的出现正成为一个严重的公共卫生问题。多粘菌素，几十年来因毒性问题而被大多放弃的抗生素，最终被认为是治疗多重耐药革兰氏阴性菌感染的最后一线治疗药物。本综述调查了对多粘菌素结构及其化学、抗菌活性和肾毒性机制、生物标志物、协同作用和与其他抗菌药物的联合作用以及抗生物膜特性的理解的进展。还讨论了新一代多粘菌素药物设计和开发的最新进展。一种新的方法考虑了对多粘菌素支架的修饰，将代谢和解毒问题纳入药物设计过程中，这是一种很有前途的新方法，可能有助于防止在肾脏中积累并降低肾毒性。
