Imperial College London
Alternate

Professor Angelika Gründling

Faculty of Medicine, Department of Infectious Disease

Professor of Molecular Microbiology
 
 
 
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Contact

 

+44 (0)20 7594 5256a.grundling Website

 
 
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Location

 

6.22Flowers buildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Zhong:2020:10.1073/pnas.2011024117,
author = {Zhong, W and Shi, Z and Mahadevegowda, SH and Liu, B and Zhang, K and Hui, Koh C and Ruan, L and Chen, Y and Zeden, MS and Pee, CJE and Marimuthu, K and Pratim, De P and Tek, Ng O and Zhu, Y and Chi, YR and Hammond, PT and Yang, L and Gan, Y-H and Pethe, K and Greenberg, EP and Grundling, A and Chan-Park, MB},
doi = {10.1073/pnas.2011024117},
journal = {Proceedings of the National Academy of Sciences of USA},
pages = {31376--31385},
title = {Designer broad-spectrum polyimidazolium antibiotics},
url = {http://dx.doi.org/10.1073/pnas.2011024117},
volume = {117},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.
AU  - Zhong,W
AU  - Shi,Z
AU  - Mahadevegowda,SH
AU  - Liu,B
AU  - Zhang,K
AU  - Hui,Koh C
AU  - Ruan,L
AU  - Chen,Y
AU  - Zeden,MS
AU  - Pee,CJE
AU  - Marimuthu,K
AU  - Pratim,De P
AU  - Tek,Ng O
AU  - Zhu,Y
AU  - Chi,YR
AU  - Hammond,PT
AU  - Yang,L
AU  - Gan,Y-H
AU  - Pethe,K
AU  - Greenberg,EP
AU  - Grundling,A
AU  - Chan-Park,MB
DO  - 10.1073/pnas.2011024117
EP  - 31385
PY  - 2020///
SN  - 0027-8424
SP  - 31376
TI  - Designer broad-spectrum polyimidazolium antibiotics
T2  - Proceedings of the National Academy of Sciences of USA
UR  - http://dx.doi.org/10.1073/pnas.2011024117
UR  - http://hdl.handle.net/10044/1/84756
VL  - 117
ER  -
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