Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin
Gram-negative bacteria are intrinsically more resistant to many frontline antibiotics, which is attributed to the permeability barrier of the outer membrane, drug efflux pumps and porins. Consequently, discovery of new small molecules antibiotics to kill drug-resistant Gram-negative bacteria present...
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| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Online Access: | https://hdl.handle.net/10356/174751 |
| _version_ | 1826126240219660288 |
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| author | Swaleeha Jaan Abdullah Mu, Yuguang Bhattacharjya, Surajit |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Swaleeha Jaan Abdullah Mu, Yuguang Bhattacharjya, Surajit |
| author_sort | Swaleeha Jaan Abdullah |
| collection | NTU |
| description | Gram-negative bacteria are intrinsically more resistant to many frontline antibiotics, which is attributed to the permeability barrier of the outer membrane, drug efflux pumps and porins. Consequently, discovery of new small molecules antibiotics to kill drug-resistant Gram-negative bacteria presents a significant challenge. Thanatin, a 21-residue insect-derived antimicrobial peptide, is known for its potent activity against Enterobacter Gram-negative bacteria, including drug-resistant strains. Here, we investigated a 15-residue N-terminal truncated analog PM15 (P1IIYCNRRTGKCQRM15) of thanatin to determine modes of action and antibacterial activity. PM15 and the P1 to Y and A substituted variants PM15Y and PM15A delineated interactions and permeabilization of the LPS-outer membrane. In antibacterial assays, PM15 and the analogs showed growth inhibition of strains of Gram-negative bacteria that is largely dependent on the composition of the culture media. Atomic-resolution structures of PM15 and PM15Y in free solution and in complex with LPS micelle exhibited persistent β-hairpin structures similar to native thanatin. However, in complex with LPS, the structures of peptides are more compact, with extensive packing interactions among residues across the two anti-parallel strands of the β-hairpin. The docked complex of PM15/LPS revealed a parallel orientation of the peptide that may be sustained by potential ionic and van der Waals interactions with the lipid A moiety of LPS. Further, PM15 and PM15Y bind to LptAm, a monomeric functional variant of LptA, the periplasmic component of the seven-protein (A-G) complex involved in LPS transport. Taken together, the structures, target interactions and antibacterial effect of PM15 presented in the current study could be useful in designing thanatin-based peptide analogs. |
| first_indexed | 2024-10-01T06:49:26Z |
| format | Journal Article |
| id | ntu-10356/174751 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:49:26Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1747512024-04-15T15:33:23Z Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin Swaleeha Jaan Abdullah Mu, Yuguang Bhattacharjya, Surajit School of Biological Sciences Medicine, Health and Life Sciences Antibiotic resistance Antimicrobial Gram-negative bacteria are intrinsically more resistant to many frontline antibiotics, which is attributed to the permeability barrier of the outer membrane, drug efflux pumps and porins. Consequently, discovery of new small molecules antibiotics to kill drug-resistant Gram-negative bacteria presents a significant challenge. Thanatin, a 21-residue insect-derived antimicrobial peptide, is known for its potent activity against Enterobacter Gram-negative bacteria, including drug-resistant strains. Here, we investigated a 15-residue N-terminal truncated analog PM15 (P1IIYCNRRTGKCQRM15) of thanatin to determine modes of action and antibacterial activity. PM15 and the P1 to Y and A substituted variants PM15Y and PM15A delineated interactions and permeabilization of the LPS-outer membrane. In antibacterial assays, PM15 and the analogs showed growth inhibition of strains of Gram-negative bacteria that is largely dependent on the composition of the culture media. Atomic-resolution structures of PM15 and PM15Y in free solution and in complex with LPS micelle exhibited persistent β-hairpin structures similar to native thanatin. However, in complex with LPS, the structures of peptides are more compact, with extensive packing interactions among residues across the two anti-parallel strands of the β-hairpin. The docked complex of PM15/LPS revealed a parallel orientation of the peptide that may be sustained by potential ionic and van der Waals interactions with the lipid A moiety of LPS. Further, PM15 and PM15Y bind to LptAm, a monomeric functional variant of LptA, the periplasmic component of the seven-protein (A-G) complex involved in LPS transport. Taken together, the structures, target interactions and antibacterial effect of PM15 presented in the current study could be useful in designing thanatin-based peptide analogs. Ministry of Education (MOE) Published version This work was supported by a grant from the Ministry of Education (MOE), RG102/20, Singapore 2024-04-09T02:51:16Z 2024-04-09T02:51:16Z 2024 Journal Article Swaleeha Jaan Abdullah, Mu, Y. & Bhattacharjya, S. (2024). Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin. Antibiotics, 13(1), 74-. https://dx.doi.org/10.3390/antibiotics13010074 2079-6382 https://hdl.handle.net/10356/174751 10.3390/antibiotics13010074 38247633 2-s2.0-85183399184 1 13 74 en RG102/20 Antibiotics © 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/). application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Antibiotic resistance Antimicrobial Swaleeha Jaan Abdullah Mu, Yuguang Bhattacharjya, Surajit Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin |
| title | Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin |
| title_full | Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin |
| title_fullStr | Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin |
| title_full_unstemmed | Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin |
| title_short | Structures, interactions and activity of the N-terminal truncated variants of antimicrobial peptide thanatin |
| title_sort | structures interactions and activity of the n terminal truncated variants of antimicrobial peptide thanatin |
| topic | Medicine, Health and Life Sciences Antibiotic resistance Antimicrobial |
| url | https://hdl.handle.net/10356/174751 |
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