Designer broad-spectrum polyimidazolium antibiotics
© 2020 National Academy of Sciences. All rights reserved. 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...
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/133954 |
| _version_ | 1811076608208928768 |
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| author | Zhong, Wenbin Shi, Zhenyu Mahadevegowda, Surendra H Liu, Bo Zhang, Kaixi Koh, Chong Hui Ruan, Lin Chen, Yahua Zeden, Merve S Pee, Carmen JE Marimuthu, Kalisvar De, Partha Pratim Ng, Oon Tek Zhu, Yabin Chi, Yonggui Robin Hammond, Paula T Yang, Liang Gan, Yunn-Hwen Pethe, Kevin Greenberg, E Peter Gründling, Angelika Chan-Park, Mary B |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Zhong, Wenbin Shi, Zhenyu Mahadevegowda, Surendra H Liu, Bo Zhang, Kaixi Koh, Chong Hui Ruan, Lin Chen, Yahua Zeden, Merve S Pee, Carmen JE Marimuthu, Kalisvar De, Partha Pratim Ng, Oon Tek Zhu, Yabin Chi, Yonggui Robin Hammond, Paula T Yang, Liang Gan, Yunn-Hwen Pethe, Kevin Greenberg, E Peter Gründling, Angelika Chan-Park, Mary B |
| author_sort | Zhong, Wenbin |
| collection | MIT |
| description | © 2020 National Academy of Sciences. All rights reserved. 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 sitedirected 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. |
| first_indexed | 2024-09-23T10:24:50Z |
| format | Article |
| id | mit-1721.1/133954 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:24:50Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1339542023-09-28T20:02:52Z Designer broad-spectrum polyimidazolium antibiotics Zhong, Wenbin Shi, Zhenyu Mahadevegowda, Surendra H Liu, Bo Zhang, Kaixi Koh, Chong Hui Ruan, Lin Chen, Yahua Zeden, Merve S Pee, Carmen JE Marimuthu, Kalisvar De, Partha Pratim Ng, Oon Tek Zhu, Yabin Chi, Yonggui Robin Hammond, Paula T Yang, Liang Gan, Yunn-Hwen Pethe, Kevin Greenberg, E Peter Gründling, Angelika Chan-Park, Mary B Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Chemical Engineering © 2020 National Academy of Sciences. All rights reserved. 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 sitedirected 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. 2021-10-27T19:57:21Z 2021-10-27T19:57:21Z 2020 2021-06-10T15:46:25Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133954 en 10.1073/pnas.2011024117 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Zhong, Wenbin Shi, Zhenyu Mahadevegowda, Surendra H Liu, Bo Zhang, Kaixi Koh, Chong Hui Ruan, Lin Chen, Yahua Zeden, Merve S Pee, Carmen JE Marimuthu, Kalisvar De, Partha Pratim Ng, Oon Tek Zhu, Yabin Chi, Yonggui Robin Hammond, Paula T Yang, Liang Gan, Yunn-Hwen Pethe, Kevin Greenberg, E Peter Gründling, Angelika Chan-Park, Mary B Designer broad-spectrum polyimidazolium antibiotics |
| title | Designer broad-spectrum polyimidazolium antibiotics |
| title_full | Designer broad-spectrum polyimidazolium antibiotics |
| title_fullStr | Designer broad-spectrum polyimidazolium antibiotics |
| title_full_unstemmed | Designer broad-spectrum polyimidazolium antibiotics |
| title_short | Designer broad-spectrum polyimidazolium antibiotics |
| title_sort | designer broad spectrum polyimidazolium antibiotics |
| url | https://hdl.handle.net/1721.1/133954 |
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