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J Phys Chem Lett. 2019 Feb 21;10(4):754-760. doi: 10.1021/acs.jpclett.8b03508. Epub 2019 Feb 5.

Distinct Intramolecular Hydrogen Bonding Dictates Antimicrobial Action of Membrane-Targeting Amphiphiles.

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Laboratory of Nanotechnology and Chemical Biology , Regional Centre for Biotechnology , NCR Biotech Science Cluster, third Milestone, Faridabad-Gurgaon Expressway , Faridabad 121001 , Haryana , India.
Manipal Academy of Higher Education , Manipal 576104 , Karnataka , India.
CSIR-Institute of Genomics and Integrative Biology , Mathura Road , New Delhi 110025 , India.
International Centre for Genetic Engineering and Biotechnology , Aruna Asaf Ali Marg , New Delhi 110067 , India.
School of Chemistry , University of Southampton , Highfield, Southampton SO17 1BJ , United Kingdom.


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.

[Indexed for MEDLINE]

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