Designer broad-spectrum polyimidazolium antibiotics

Zhong，Wenbin1,2; Shi，Zhenyu1,2; Mahadevegowda，Surendra H.1,2; Liu，Bo1,2; Zhang，Kaixi1,2; Koh，Chong Hui1,2; Ruan，Lin1,2; Chen，Yahua3; Zeden，Merve S.4; Pee，Carmen J.E.5; Marimuthu，Kalisvar6,7; De，Partha Pratim8; Ng，Oon Tek5,6,7; Zhu，Yabin9; Chi，Yonggui Robin10; Hammond，Paula T.11,12; Yang，Liang13,14; Gan，Yunn Hwen3; Pethe，Kevin2,5,15; Greenberg，E. Peter16; Gründling，Angelika17; Chan-Park，Mary B.2,5,18

2020-12-08

10.1073/pnas.2011024117

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   影响因子和分区

0027-8424

1091-6490

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.

bactericidal cationic antimicrobial polymers colistin-resistant

SCI

英语

NI论文

其他

Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 3["MOE2013-T3-1-002","MOE2018-T3-1-003"] ; Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 2[MOE2017-T2-1-063] ; Wellcome Trust["100289/Z/12/Z","210671/Z/18/Z"] ; Major Project of 2025 Sci & Tech Innovation of Ningbo, China[2018B10052]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000598990900020

NATL ACAD SCIENCES

BIOLOGY & BIOCHEMISTRY;CLINICAL MEDICINE;MULTIDISCIPLINARY;PLANT & ANIMAL SCIENCE;ENVIRONMENT/ECOLOGY;SOCIAL SCIENCES, GENERAL;MICROBIOLOGY;ECONOMICS BUSINESS;IMMUNOLOGY;MATERIALS SCIENCE;MATHEMATICS;SPACE SCIENCE;MOLECULAR BIOLOGY & GENETICS;PHARMACOLOGY & TOXICOLOGY;CHEMISTRY;PSYCHIATRY/PSYCHOLOGY;NEUROSCIENCE & BEHAVIOR;PHYSICS;GEOSCIENCES;AGRICULTURAL SCIENCES;ENGINEERING

2-s2.0-85097585004

Scopus

1.School of Chemical and Biomedical Engineering,Nanyang Technological University,637459,Singapore
2.Centre for Antimicrobial Bioengineering,Nanyang Technological University,637459,Singapore
3.Department of Biochemistry,National University of Singapore,117596,Singapore
4.Section of Molecular Microbiology and Medical Research Council Centre for Molecular Bacteriology and Infection,Imperial College London,London,SW7 2AZ,United Kingdom
5.Lee Kong Chian School of Medicine,Nanyang Technological University,636921,Singapore
6.Department of Infectious Diseases,Tan Tock Seng Hospital,308433,Singapore
7.National Centre for Infectious Diseases,308442,Singapore
8.Department of Laboratory Medicine,Tan Tock Seng Hospital,308433,Singapore
9.Medical School of Ningbo University,Ningbo University,Ningbo,315211,China
10.Division of Chemistry & Biological Chemistry,Nanyang Technological University,637371,Singapore
11.Koch Institute for Integrative Cancer Research,Massachusetts Institute of Technology,Cambridge,MA 02139,
12.Department of Chemical Engineering,Massachusetts Institute of Technology,Cambridge,MA 02139,
13.School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
14.Singapore Centre for Environmental Life Sciences Engineering,Nanyang Technological University,637551,Singapore
15.School of Biological Sciences,Nanyang Technological University,637551,Singapore
16.Department of Microbiology, University of Washington, Seattle, WA 98195 epgreen@uw.edu a.grundling@imperial.ac.uk mbechan@ntu.edu.sg
17.Section of Molecular Microbiology and Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, United Kingdom; epgreen@uw.edu a.grundling@imperial.ac.uk mbechan@ntu.edu.sg
18.School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459; epgreen@uw.edu a.grundling@imperial.ac.uk mbechan@ntu.edu.sg

Zhong，Wenbin,Shi，Zhenyu,Mahadevegowda，Surendra H.,et al. Designer broad-spectrum polyimidazolium antibiotics[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2020,117(49):31376-31385.

Zhong，Wenbin.,Shi，Zhenyu.,Mahadevegowda，Surendra H..,Liu，Bo.,Zhang，Kaixi.,...&Chan-Park，Mary B..(2020).Designer broad-spectrum polyimidazolium antibiotics.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,117(49),31376-31385.

Zhong，Wenbin,et al."Designer broad-spectrum polyimidazolium antibiotics".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 117.49(2020):31376-31385.