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Title: Linking dual mode of action of host defense antimicrobial peptide thanatin: structures, lipopolysaccharide and LptAm binding of designed analogs
Authors: Sinha, Sheetal
Dhanabal, Vidhya Bharathi
Sperandeo, Paola
Polissi, Alessandra
Bhattacharjya, Surajit
Keywords: Science::Biological sciences::Biophysics
Issue Date: 2022
Source: Sinha, S., Dhanabal, V. B., Sperandeo, P., Polissi, A. & Bhattacharjya, S. (2022). Linking dual mode of action of host defense antimicrobial peptide thanatin: structures, lipopolysaccharide and LptAm binding of designed analogs. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1864(3), 183839-.
Journal: Biochimica et Biophysica Acta (BBA) - Biomembranes 
Abstract: At present, antibiotics options to cure infections caused by drug resistant Gram-negative pathogens are highly inadequate. LPS outer membrane, proteins involved in LPS transport and biosynthesis pathways are vital targets. Thanatin, an insect derived 21-residue long antimicrobial peptide may be exploited for the development of effective antibiotics against Gram-negative bacteria. As a mode of bacterial cell killing, thanatin disrupts LPS outer membrane and inhibits LPS transport by binding to the periplasmic protein LptAm. Here, we report structure-activity correlation of thanatin and analogs for the purpose of rational design. These analogs of thanatin are investigated, by NMR, ITC and fluorescence, to correlate structure, antibacterial activity and binding with LPS and LptAm, a truncated monomeric variant. Our results demonstrate that an analog thanatin M21F exhibits superior antibacterial activity. In LPS interaction analyses, thanatin M21F demonstrate high affinity binding to outer membrane LPS. The atomic resolution structure of thanatin M21F in LPS micelle reveals four stranded -sheet structure in a dimeric topology whereby the sidechain of aromatic residues Y10, F21 sustained mutual packing at the interface. Strikingly, LptAm binding affinity of thanatin M21F has been significantly increased with an estimated Kd~0.73 nM vs 13 nM for thanatin. Further, atomic resolution structures and interactions of Ala based thanatin analogs define plausible correlations with antibacterial activity and LPS, LptAm interactions. Taken together, the current work provides a frame-work for the designing of thanatin based potent antimicrobial peptides for the treatment of drug resistance Gram-negative bacteria.
ISSN: 0005-2736
DOI: 10.1016/j.bbamem.2021.183839
Schools: School of Biological Sciences 
Interdisciplinary Graduate School (IGS) 
Research Centres: Nanyang Environment and Water Research Institute 
Advanced Environmental Biotechnology Centre (AEBC) 
Rights: © 2021 Elsevier B.V. All rights reserved. This paper was published in Biochimica et Biophysica Acta (BBA) - Biomembranes and is made available with permission of Elsevier B.V.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:IGS Journal Articles
NEWRI Journal Articles
SBS Journal Articles

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