Designer broad-spectrum polyimidazolium antibiotics
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...
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| Format: | Journal Article |
| Language: | English |
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2021
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| Online Access: | https://hdl.handle.net/10356/154101 |
| _version_ | 1824456965120589824 |
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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 J. E. Marimuthu, Kalisvar De, Partha Pratim Ng, Oon Tek Zhu, Yabin Chi, Robin Yonggui Hammond, Paula T. Yang, Liang Gan, Yunn-Hwen Pethe, Kevin Greenberg, E. Peter Gründling, Angelika Chan-Park, Mary B. |
| author2 | School of Chemical and Biomedical Engineering |
| author_facet | School of Chemical and Biomedical Engineering Zhong, Wenbin Shi, Zhenyu Mahadevegowda, Surendra H. Liu, Bo Zhang, Kaixi Koh, Chong Hui Ruan, Lin Chen, Yahua Zeden, Merve S. Pee, Carmen J. E. Marimuthu, Kalisvar De, Partha Pratim Ng, Oon Tek Zhu, Yabin Chi, Robin Yonggui Hammond, Paula T. Yang, Liang Gan, Yunn-Hwen Pethe, Kevin Greenberg, E. Peter Gründling, Angelika Chan-Park, Mary B. |
| author_sort | Zhong, Wenbin |
| collection | NTU |
| description | 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. |
| first_indexed | 2025-02-19T04:02:29Z |
| format | Journal Article |
| id | ntu-10356/154101 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T04:02:29Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1541012022-01-01T20:12:13Z 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 J. E. Marimuthu, Kalisvar De, Partha Pratim Ng, Oon Tek Zhu, Yabin Chi, Robin Yonggui Hammond, Paula T. Yang, Liang Gan, Yunn-Hwen Pethe, Kevin Greenberg, E. Peter Gründling, Angelika Chan-Park, Mary B. School of Chemical and Biomedical Engineering Lee Kong Chian School of Medicine (LKCMedicine) School of Physical and Mathematical Sciences School of Biological Sciences Singapore Centre for Environmental Life Sciences and Engineering (SCELSE) Centre for Antimicrobial Bioengineering Engineering::Chemical engineering::Polymers and polymer manufacture Cationic Antimicrobial Polymers Bactericidal 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. Ministry of Education (MOE) Published version This research was supported by the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 3 (Grants MOE2013- T3-1-002 and MOE2018-T3-1-003) and Tier 2 (Grant MOE2017-T2-1-063) and by the Major Project of 2025 Sci &Tech Innovation of Ningbo, China (2018B10052) and the Wellcome Trust Grants 100289/Z/12/Z and 210671/Z/ 18/Z to A.G., M.S.Z. was supported by a Medical Research Council Centre for Molecular Bacteriology and Infection (MRC CMBI) studentship. 2021-12-15T04:51:41Z 2021-12-15T04:51:41Z 2020 Journal Article Zhong, W., Shi, Z., Mahadevegowda, S. H., Liu, B., Zhang, K., Koh, C. H., Ruan, L., Chen, Y., Zeden, M. S., Pee, C. J. E., Marimuthu, K., De, P. P., Ng, O. T., Zhu, Y., Chi, R. Y., Hammond, P. T., Yang, L., Gan, Y., Pethe, K., ...Chan-Park, M. B. (2020). Designer broad-spectrum polyimidazolium antibiotics. Proceedings of the National Academy of Sciences (PNAS), 117(49), 31376-31385. https://dx.doi.org/10.1073/pnas.2011024117 0027-8424 https://hdl.handle.net/10356/154101 10.1073/pnas.2011024117 49 117 31376 31385 en MOE2013- T3-1-002 MOE2018-T3-1-003 MOE2017-T2-1-063 Proceedings of the National Academy of Sciences (PNAS) © 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). application/pdf application/pdf |
| spellingShingle | Engineering::Chemical engineering::Polymers and polymer manufacture Cationic Antimicrobial Polymers Bactericidal Zhong, Wenbin Shi, Zhenyu Mahadevegowda, Surendra H. Liu, Bo Zhang, Kaixi Koh, Chong Hui Ruan, Lin Chen, Yahua Zeden, Merve S. Pee, Carmen J. E. Marimuthu, Kalisvar De, Partha Pratim Ng, Oon Tek Zhu, Yabin Chi, Robin Yonggui 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 |
| topic | Engineering::Chemical engineering::Polymers and polymer manufacture Cationic Antimicrobial Polymers Bactericidal |
| url | https://hdl.handle.net/10356/154101 |
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