Multifaceted Activity of Fabimycin: Insights from Molecular Dynamics Studies on Bacterial Membrane Models

Membranescells’ essential scaffoldsare
valid
molecular targets for substances with an antimicrobial effect. While
certain substances, such as octenidine, have been developed to target
membranes for antimicrobial purposes, the recently reported molecule,
fabimycin (F2B)a novel agent targeting drug-resistant Gram-negative
bacteriahas not received adequate attention regarding its
activity on membranes in the literature. The following study aims
to investigate the effects of F2B on different bacterial membrane
models, including simple planar bilayers and more complex bilayer
systems that mimic the Escherichia coli shell equipped with double inner and outer bilayers. Our results
show that F2B exhibited more pronounced interactions with bacterial
membrane systems compared to the control PC system. Furthermore, we
observed significant changes in local membrane property homeostasis
in both the inner and outer membrane models, specifically in the case
of lateral diffusion, membrane thickness, and membrane resilience
(compressibility, tilt). Finally, our results showed that the effect
of F2B differed in a complex system and a single membrane system.
Our study provides new insights into the multifaceted activity of
F2B, demonstrating its potential to disrupt bacterial membrane homeostasis,
indicating that its activity extends the currently known mechanism
of FabI enzyme inhibition. This disruption, coupled with the ability
of F2B to penetrate the outer membrane layers, sheds new light on
the behavior of this antimicrobial molecule. This highlights the importance
of the interaction with the membrane, crucial in combating bacterial
infections, particularly those caused by drug-resistant strains.