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.