  Gram-negative bacteria are a serious health concern due to the strong
multidrug resistance that they display, partly due to the presence of a
permeability barrier comprising two membranes with active efflux. New
approaches are urgently needed to design antibiotics effective against these
pathogens. In this work, we present a novel topological fragment-based approach
("Hunting Fragments Of X" or "Hunting FOX") to rationally "hunt for" chemical
fragments that promote compound ability to permeate the outer membrane. Our
approach generalizes to other drug design applications. We measure minimum
inhibitory concentrations of compounds in two strains of Pseudomonas aeruginosa
with variable permeability barriers and use them as an input to the Hunting FOX
algorithm to identify molecular fragments responsible for enhanced outer
membrane permeation properties and candidate molecules from an external library
that demonstrate good permeation ability. Overall, we present proof of concept
for a novel method that is expected to be valuable for rational design of
hybrid drugs.
