Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/174876
Title: Outer-membrane permeabilization, LPS transport inhibition: activity, interactions, and structures of thanatin derived antimicrobial peptides
Authors: Swaleeha Jaan Abdullah
Yan, Bernice Tan Siu
Palanivelu, Nithya
Dhanabal, Vidhya Bharathi
Bifani, Juan Pablo
Bhattacharjya, Surajit
Keywords: Medicine, Health and Life Sciences
Issue Date: 2024
Source: Swaleeha Jaan Abdullah, Yan, B. T. S., Palanivelu, N., Dhanabal, V. B., Bifani, J. P. & Bhattacharjya, S. (2024). Outer-membrane permeabilization, LPS transport inhibition: activity, interactions, and structures of thanatin derived antimicrobial peptides. International Journal of Molecular Sciences, 25(4), 2122-. https://dx.doi.org/10.3390/ijms25042122
Project: RG102/20 
Journal: International Journal of Molecular Sciences 
Abstract: Currently, viable antibiotics available to mitigate infections caused by drug-resistant Gram-negative bacteria are highly limited. Thanatin, a 21-residue-long insect-derived antimicrobial peptide (AMP), is a promising lead molecule for the potential development of novel antibiotics. Thanatin is extremely potent, particularly against the Enterobacter group of Gram-negative pathogens, e.g., E. coli and K. pneumoniae. As a mode of action, cationic thanatin efficiently permeabilizes the LPS-outer membrane and binds to the periplasmic protein LptAm to inhibit outer membrane biogenesis. Here, we have utilized N-terminal truncated 16- and 14-residue peptide fragments of thanatin and investigated structure, activity, and selectivity with correlating modes of action. A designed 16-residue peptide containing D-Lys (dk) named VF16 (V1PIIYCNRRT-dk-KCQRF16) demonstrated killing activity in Gram-negative bacteria. The VF16 peptide did not show any detectable toxicity to the HEK 293T cell line and kidney cell line Hep G2. As a mode of action, VF16 interacted with LPS, permeabilizing the outer membrane and binding to LptAm with high affinity. Atomic-resolution structures of VF16 in complex with LPS revealed cationic and aromatic surfaces involved in outer membrane interactions and permeabilization. Further, analyses of an inactive 14-residue native thanatin peptide (IM14: IIYCNRRTGKCQRM) delineated the requirement of the β-sheet structure in activity and target interactions. Taken together, this work would pave the way for the designing of short analogs of thanatin-based antimicrobials.
URI: https://hdl.handle.net/10356/174876
ISSN: 1661-6596
DOI: 10.3390/ijms25042122
Schools: School of Biological Sciences 
Rights: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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