A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening

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2021
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Jiang, Xukai
Patil, Nitin A.
Azad, Mohammad A. K.
Wickremasinghe, Hasini
Yu, Heidi
Zhao, Jinxin
Zhang, Xinru
Li, Mengyao
Li, Jian
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Multidrug-resistant Gram-negative bacteria represent a major medical challenge worldwide. New antibiotics are desperately required with ‘old’ polymyxins often being the only available therapeutic option. Here, we systematically investigated the structure–activity relationship (SAR) of polymyxins using a quantitative lipidomics-informed outer membrane (OM) model of Acinetobacter baumannii and a series of chemically synthesized polymyxin analogs. By integrating chemical biology and all-atom molecular dynamics simulations, we deciphered how each residue of the polymyxin molecule modulated its conformational folding and specific interactions with the bacterial OM. Importantly, a novel designed polymyxin analog FADDI-287 with predicted stronger OM penetration showed improved in vitro antibacterial activity. Collectively, our study provides a novel chemical biology and computational strategy to expedite the discovery of new-generation polymyxins against life-threatening Gram-negative ‘superbugs’.

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ISO 690JIANG, Xukai, Nitin A. PATIL, Mohammad A. K. AZAD, Hasini WICKREMASINGHE, Heidi YU, Jinxin ZHAO, Xinru ZHANG, Mengyao LI, Falk SCHREIBER, Jian LI, 2021. A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening. In: Chemical Science. Royal Society of Chemistry (RSC). 2021, 12(36), pp. 12211-12220. ISSN 2041-6520. eISSN 2041-6539. Available under: doi: 10.1039/D1SC03460J
BibTex
@article{Jiang2021-09-22novel-54713,
  year={2021},
  doi={10.1039/D1SC03460J},
  title={A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening},
  number={36},
  volume={12},
  issn={2041-6520},
  journal={Chemical Science},
  pages={12211--12220},
  author={Jiang, Xukai and Patil, Nitin A. and Azad, Mohammad A. K. and Wickremasinghe, Hasini and Yu, Heidi and Zhao, Jinxin and Zhang, Xinru and Li, Mengyao and Schreiber, Falk and Li, Jian}
}
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