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Distinct intramolecular hydrogen bonding dictates antimicrobial action of membrane-targeting amphiphiles

Distinct intramolecular hydrogen bonding dictates antimicrobial action of membrane-targeting amphiphiles
Distinct intramolecular hydrogen bonding dictates antimicrobial action of membrane-targeting amphiphiles

As mechanisms underpinning the molecular interactions between membrane-targeting antimicrobials and Gram-negative bacterial membranes at atomistic scale remain elusive, we used cholic acid (CA)-derived amphiphiles with different hydrophobicities as model antimicrobials and assessed the effect of their conformational flexibility on antimicrobial activity. Relative to other hydrophobic counterparts, a compound with a hexyl chain (6) showed the strongest binding with the lipopolysaccharide (LPS) of Gram-negative bacterial membranes and acted as an effective antimicrobial. Biomolecular simulations, validated by complementary approaches, revealed that specific intramolecular hydrogen bonding imparts conformationally rigid character to compound 6. This conformational stability of compound 6 allows minimum but specific interactions of the amphiphile with LPS that are a sum of exothermic processes like electrostatic interactions, membrane insertion, and endothermic contributions from disaggregation of LPS. Therefore, our study reveals that a membrane-targeting mechanism with the help of conformationally selective molecules offers a roadmap for developing future therapeutics against bacterial infections.

1948-7185
754-760
Mitra, Madhurima
9a6a4fe6-5649-4e2a-b5ab-6e4a1c283787
Asad, Mohammad
242af30b-e42c-4197-b5b5-3319e663c9de
Kumar, Sandeep
8ca9f9d9-c51e-44f7-862e-ec761969d89a
Yadav, Kavita
67269c43-9473-4131-bea2-e28f37a1c029
Chaudhary, Sarika
26e39950-19d6-4842-b09d-14f10cc8e904
Bhavesh, Neel Sarovar
6f660ce1-f092-40ff-a88a-9a4a65736a23
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Thukral, Lipi
334e3eb2-3313-4b5c-9cc9-8ea852947518
Bajaj, Avinash
304e917c-3352-4aa1-938d-7f0fbf74fa1f
Mitra, Madhurima
9a6a4fe6-5649-4e2a-b5ab-6e4a1c283787
Asad, Mohammad
242af30b-e42c-4197-b5b5-3319e663c9de
Kumar, Sandeep
8ca9f9d9-c51e-44f7-862e-ec761969d89a
Yadav, Kavita
67269c43-9473-4131-bea2-e28f37a1c029
Chaudhary, Sarika
26e39950-19d6-4842-b09d-14f10cc8e904
Bhavesh, Neel Sarovar
6f660ce1-f092-40ff-a88a-9a4a65736a23
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Thukral, Lipi
334e3eb2-3313-4b5c-9cc9-8ea852947518
Bajaj, Avinash
304e917c-3352-4aa1-938d-7f0fbf74fa1f

Mitra, Madhurima, Asad, Mohammad, Kumar, Sandeep, Yadav, Kavita, Chaudhary, Sarika, Bhavesh, Neel Sarovar, Khalid, Syma, Thukral, Lipi and Bajaj, Avinash (2019) Distinct intramolecular hydrogen bonding dictates antimicrobial action of membrane-targeting amphiphiles. The Journal of Physical Chemistry Letters, 10 (4), 754-760. (doi:10.1021/acs.jpclett.8b03508).

Record type: Article

Abstract

As mechanisms underpinning the molecular interactions between membrane-targeting antimicrobials and Gram-negative bacterial membranes at atomistic scale remain elusive, we used cholic acid (CA)-derived amphiphiles with different hydrophobicities as model antimicrobials and assessed the effect of their conformational flexibility on antimicrobial activity. Relative to other hydrophobic counterparts, a compound with a hexyl chain (6) showed the strongest binding with the lipopolysaccharide (LPS) of Gram-negative bacterial membranes and acted as an effective antimicrobial. Biomolecular simulations, validated by complementary approaches, revealed that specific intramolecular hydrogen bonding imparts conformationally rigid character to compound 6. This conformational stability of compound 6 allows minimum but specific interactions of the amphiphile with LPS that are a sum of exothermic processes like electrostatic interactions, membrane insertion, and endothermic contributions from disaggregation of LPS. Therefore, our study reveals that a membrane-targeting mechanism with the help of conformationally selective molecules offers a roadmap for developing future therapeutics against bacterial infections.

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Revised MS JPCL-UnMarked - Accepted Manuscript
Restricted to Repository staff only until 29 January 2020.
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Final Revised SI JPCL
Restricted to Repository staff only until 29 January 2020.
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More information

Accepted/In Press date: 29 January 2019
e-pub ahead of print date: 29 January 2019
Published date: 21 February 2019

Identifiers

Local EPrints ID: 429277
URI: https://eprints.soton.ac.uk/id/eprint/429277
ISSN: 1948-7185
PURE UUID: c3d3c56a-6c14-49b0-9406-de7e7c741311
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

Catalogue record

Date deposited: 25 Mar 2019 17:30
Last modified: 22 Oct 2019 00:42

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