Gray Declan Alan, Wenzel Michaela
Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Division of Chemical Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden.
Antibiotics (Basel). 2020 Jan 3;9(1):17. doi: 10.3390/antibiotics9010017.
Daptomycin is a cyclic lipopeptide antibiotic, which was discovered in 1987 and entered the market in 2003. To date, it serves as last resort antibiotic to treat complicated skin infections, bacteremia, and right-sided endocarditis caused by Gram-positive pathogens, most prominently methicillin-resistant . Daptomycin was the last representative of a novel antibiotic class that was introduced to the clinic. It is also one of the few membrane-active compounds that can be applied systemically. While membrane-active antibiotics have long been limited to topical applications and were generally excluded from systemic drug development, they promise slower resistance development than many classical drugs that target single proteins. The success of daptomycin together with the emergence of more and more multi-resistant superbugs attracted renewed interest in this compound class. Studying daptomycin as a pioneering systemic membrane-active compound might help to pave the way for future membrane-targeting antibiotics. However, more than 30 years after its discovery, the exact mechanism of action of daptomycin is still debated. In particular, there is a prominent discrepancy between in vivo and in vitro studies. In this review, we discuss the current knowledge on the mechanism of daptomycin against Gram-positive bacteria and try to offer explanations for these conflicting observations.
达托霉素是一种环脂肽抗生素，于1987年被发现，并于2003年进入市场。迄今为止，它是治疗由革兰氏阳性病原体引起的复杂性皮肤感染、菌血症和右侧心内膜炎的最后一道抗生素防线，最主要的是耐甲氧西林的病原体。达托霉素是引入临床的新型抗生素类别的最后一个代表。它也是少数几种可全身应用的膜活性化合物之一。虽然膜活性抗生素长期以来仅限于局部应用，并且通常被排除在全身药物开发之外，但与许多靶向单一蛋白质的传统药物相比，它们有望减缓耐药性的发展。达托霉素的成功以及越来越多的多重耐药超级细菌的出现，重新引发了人们对这类化合物的兴趣。将达托霉素作为一种开创性的全身膜活性化合物进行研究，可能有助于为未来的膜靶向抗生素铺平道路。然而，在其发现30多年后，达托霉素的确切作用机制仍存在争议。特别是，体内和体外研究之间存在明显差异。在这篇综述中，我们讨论了目前关于达托霉素抗革兰氏阳性菌机制的知识，并试图为这些相互矛盾的观察结果提供解释。
