Pyne Alice, Pfeil Marc-Philipp, Bennett Isabel, Ravi Jascindra, Iavicoli Patrizia, Lamarre Baptiste, Roethke Anita, Ray Santanu, Jiang Haibo, Bella Angelo, Reisinger Bernd, Yin Daniel, Little Benjamin, Muñoz-García Juan C, Cerasoli Eleonora, Judge Peter J, Faruqui Nilofar, Calzolai Luigi, Henrion Andre, Martyna Glenn J, Grovenor Chris R M, Crain Jason, Hoogenboom Bart W, Watts Anthony, Ryadnov Maxim G
National Physical Laboratory , Teddington , Middlesex TW11 0LW , UK . Email:
London Centre for Nanotechnology and Department of Physics and Astronomy , University College London , London WC1E 6BT , UK.
Chem Sci. 2017 Feb 1;8(2):1105-1115. doi: 10.1039/c6sc02925f. Epub 2016 Sep 26.
The spread of bacterial resistance to traditional antibiotics continues to stimulate the search for alternative antimicrobial strategies. All forms of life, from bacteria to humans, are postulated to rely on a fundamental host defense mechanism, which exploits the formation of open pores in microbial phospholipid bilayers. Here we predict that transmembrane poration is not necessary for antimicrobial activity and reveal a distinct poration mechanism that targets the outer leaflet of phospholipid bilayers. Using a combination of molecular-scale and real-time imaging, spectroscopy and spectrometry approaches, we introduce a structural motif with a universal insertion mode in reconstituted membranes and live bacteria. We demonstrate that this motif rapidly assembles into monolayer pits that coalesce during progressive membrane exfoliation, leading to bacterial cell death within minutes. The findings offer a new physical basis for designing effective antibiotics.
细菌对传统抗生素耐药性的传播持续推动着对替代抗菌策略的探索。从细菌到人类的所有生命形式，都被假定依赖于一种基本的宿主防御机制，该机制利用微生物磷脂双层中开放孔的形成。在此，我们预测跨膜成孔对于抗菌活性并非必要，并揭示了一种针对磷脂双层外小叶的独特成孔机制。通过结合分子尺度和实时成像、光谱学和光谱测定方法，我们在重构膜和活细菌中引入了一种具有通用插入模式的结构基序。我们证明，这种基序能迅速组装成单层凹坑，在渐进性膜剥落过程中合并，导致细菌细胞在数分钟内死亡。这些发现为设计有效的抗生素提供了新的物理基础。
