Published in the journal Nature, the groundbreaking study conducted by Pahil, Gilman et al. from Harvard University's Department of Chemistry and Chemical Biology has unveiled a novel understanding of how a new antibiotic operates, providing a potential solution to antibiotic resistance.
Background: Unveiling the Microscopic Battlefield
Gram-negative bacteria, notorious for their antibiotic resistance, possess a formidable defense mechanism in the form of lipopolysaccharides (LPS). These large molecules, consisting of fatty acyl chains and sometimes hundreds of sugars, form a protective outer membrane or leaflet. This shield not only blocks various antibiotics but can also induce fever and shock in infected hosts.
A prior discovery by researchers at Roche Innovation Center identified a family of large peptides capable of targeting the lipopolysaccharide transport (Lpt) machinery in Acinetobacter, a genus of gram-negative bacteria notorious for antibiotic-resistant strains. Pahil, Gilman, et al. furthered this exploration, delving into the mechanism of action of these promising antibiotics in their new paper.
The Study: Peering into the Microscopic Realm
Using a cutting-edge technique called cryo-electron microscopy (cryo-EM), Pahil, Gilman, et al. gained insights into the molecular interactions at play on the outer membranes of the target bacteria. Like a traditional camera measures light wavelengths, cryo-EM bombards biomolecules with fine electron beams and visualizes the reflected wavelengths. They characterized the binding of macrocyclic peptides, revealing a distinct preference for affixing to components of LPS transporters only when they are actively bound to LPS.
Pahil, Gilman, et al. 2024 Nature Altered by Amielle Moreno
Findings: Molecular Glues Gums Up The Outer Structure
The study revealed that the macrocyclic peptides acted as molecular glues, trapping LPS and stalling the vital LPS transport machinery.
Interestingly, the researchers found that "the drug does not act by depleting LPS from the outer membrane because these cells can live without any LPS in the outer membrane." Instead, they caused a "toxic accumulation" of trapped LPS within the multiple layers of the bacterial outer leaflet, ultimately leading to bacterial death.
Future Directions: Same Strategy, Different Transporters
While the identified drugs proved specific for Acinetobacter, the authors highlight a significant prospect: "The mechanism of these molecular glues provides a roadmap for the development of other compounds that bind a transporter and its substrate simultaneously to block lipid transport in prokaryotic and eukaryotic systems."
The microscopic battlefield against bacterial resistance may have found its champions in macrocyclic peptides. By better understanding the finer mechanisms of microbiology, Pahil, Gilman, et al. learned how to gum up the works for gram-negative bacteria and opened the door to a new approach to antibiotic development. Tailoring this approach to new bacteria is a potent strategy to extend these findings beyond the original targets and provide a promising avenue for combating antibiotic-resistant strains.
Sources: Nature (1)(2)(3), Chemistry World
