Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria
Dissecting the complexities of branched peptide-lipopolysaccharides (LPS) interactions provide rationale for the development of non-cytotoxic antibiotic adjuvants. Using various biophysical methods, we show that the branched peptide, B2088, binds to lipid A and disrupts the supramolecular organizati...
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sg-ntu-dr.10356-847262023-02-28T17:01:16Z Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria Lakshminarayanan, Rajamani Tan, Wei Xiang Aung, Thet Tun Goh, Eunice Tze Leng Muruganantham, Nandhakumar Li, Jianguo Chang, Jamie Ya Ting Dikshit, Neha Saraswathi, Padmanabhan Lim, Rayne Rui Kang, Tse Siang Balamuralidhar, Vanniarajan Sukumaran, Bindu Verma, Chandra S. Sivaraman, Jayaraman Chaurasia, Shyam Sunder Liu, Shouping Beuerman, Roger W. School of Biological Sciences Antibiotics Bacterial infection Dissecting the complexities of branched peptide-lipopolysaccharides (LPS) interactions provide rationale for the development of non-cytotoxic antibiotic adjuvants. Using various biophysical methods, we show that the branched peptide, B2088, binds to lipid A and disrupts the supramolecular organization of LPS. The disruption of outer membrane in an intact bacterium was demonstrated by fluorescence spectroscopy and checkerboard assays, the latter confirming strong to moderate synergism between B2088 and various classes of antibiotics. The potency of synergistic combinations of B2088 and antibiotics was further established by time-kill kinetics, mammalian cell culture infections model and in vivo model of bacterial keratitis. Importantly, B2088 did not show any cytotoxicity to corneal epithelial cells for at least 96 h continuous exposure or hemolytic activity even at 20 mg/ml. Peptide congeners containing norvaline, phenylalanine and tyrosine (instead of valine in B2088) displayed better synergism compared to other substitutions. We propose that high affinity and subsequent disruption of the supramolecular assembly of LPS by the branched peptides are vital for the development of non-cytotoxic antibiotic adjuvants that can enhance the accessibility of conventional antibiotics to the intracellular targets, decrease the antibiotic consumption and holds promise in averting antibiotic resistance. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Published version 2016-12-23T08:23:14Z 2019-12-06T15:50:20Z 2016-12-23T08:23:14Z 2019-12-06T15:50:20Z 2016 Journal Article Lakshminarayanan, R., Tan, W. X., Aung, T. T., Goh, E. T. L., Muruganantham, N., Li, J., et al. (2016). Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria. Scientific Reports, 6, 25905-. 2045-2322 https://hdl.handle.net/10356/84726 http://hdl.handle.net/10220/41946 10.1038/srep25905 27174567 en Scientific Reports This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ 17 p. application/pdf |
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Antibiotics Bacterial infection Lakshminarayanan, Rajamani Tan, Wei Xiang Aung, Thet Tun Goh, Eunice Tze Leng Muruganantham, Nandhakumar Li, Jianguo Chang, Jamie Ya Ting Dikshit, Neha Saraswathi, Padmanabhan Lim, Rayne Rui Kang, Tse Siang Balamuralidhar, Vanniarajan Sukumaran, Bindu Verma, Chandra S. Sivaraman, Jayaraman Chaurasia, Shyam Sunder Liu, Shouping Beuerman, Roger W. Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria |
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Dissecting the complexities of branched peptide-lipopolysaccharides (LPS) interactions provide rationale for the development of non-cytotoxic antibiotic adjuvants. Using various biophysical methods, we show that the branched peptide, B2088, binds to lipid A and disrupts the supramolecular organization of LPS. The disruption of outer membrane in an intact bacterium was demonstrated by fluorescence spectroscopy and checkerboard assays, the latter confirming strong to moderate synergism between B2088 and various classes of antibiotics. The potency of synergistic combinations of B2088 and antibiotics was further established by time-kill kinetics, mammalian cell culture infections model and in vivo model of bacterial keratitis. Importantly, B2088 did not show any cytotoxicity to corneal epithelial cells for at least 96 h continuous exposure or hemolytic activity even at 20 mg/ml. Peptide congeners containing norvaline, phenylalanine and tyrosine (instead of valine in B2088) displayed better synergism compared to other substitutions. We propose that high affinity and subsequent disruption of the supramolecular assembly of LPS by the branched peptides are vital for the development of non-cytotoxic antibiotic adjuvants that can enhance the accessibility of conventional antibiotics to the intracellular targets, decrease the antibiotic consumption and holds promise in averting antibiotic resistance. |
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School of Biological Sciences |
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School of Biological Sciences Lakshminarayanan, Rajamani Tan, Wei Xiang Aung, Thet Tun Goh, Eunice Tze Leng Muruganantham, Nandhakumar Li, Jianguo Chang, Jamie Ya Ting Dikshit, Neha Saraswathi, Padmanabhan Lim, Rayne Rui Kang, Tse Siang Balamuralidhar, Vanniarajan Sukumaran, Bindu Verma, Chandra S. Sivaraman, Jayaraman Chaurasia, Shyam Sunder Liu, Shouping Beuerman, Roger W. |
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Article |
author |
Lakshminarayanan, Rajamani Tan, Wei Xiang Aung, Thet Tun Goh, Eunice Tze Leng Muruganantham, Nandhakumar Li, Jianguo Chang, Jamie Ya Ting Dikshit, Neha Saraswathi, Padmanabhan Lim, Rayne Rui Kang, Tse Siang Balamuralidhar, Vanniarajan Sukumaran, Bindu Verma, Chandra S. Sivaraman, Jayaraman Chaurasia, Shyam Sunder Liu, Shouping Beuerman, Roger W. |
author_sort |
Lakshminarayanan, Rajamani |
title |
Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria |
title_short |
Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria |
title_full |
Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria |
title_fullStr |
Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria |
title_full_unstemmed |
Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria |
title_sort |
branched peptide, b2088, disrupts the supramolecular organization of lipopolysaccharides and sensitizes the gram-negative bacteria |
publishDate |
2016 |
url |
https://hdl.handle.net/10356/84726 http://hdl.handle.net/10220/41946 |
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1759852921508331520 |