(56e) Modulating Pseudomonas aeruginosa Bacterial Communication with Nanoformulated Signaling Agents

Quorum-sensing (QS) therapeutics, which disable pathogen virulence
without directly killing the target pathogen, offer a means of treating
bacterial infection without creating the life/death selective pressure that in
turn may lead to antibiotic resistance among bacteria. One infection of
interest, pulmonary Pseudomonas
aeruginosa, stands to benefit from these QS therapies; however, the
bacteria exist in a biofilm state under a dense layer of pulmonary mucus,
through which the QS therapeutic must be delivered at sufficiently high
concentrations for effective treatment. We here demonstrate that the block
copolymer-directed self-assembly technique Flash NanoPrecipitation (FNP) may be
employed to create a series of nanoparticle (NP) formulations encapsulating
V-06-18, a P. aeruginosa QS agent.
Formulated nanoparticles reduce P.
aeruginosa virulence factor production by as much as two orders magnitude
more effectively than equivalently delivered but non-encapsulated drug. Pyocyanin toxin production and biofilm formation are nearly
completely inhibited with micromolar concentrations
of the nanoformulated compound. Formed nanoparticles
offer controlled release with characteristic release rates as low as two weeks,
which may be used for sustained release therapeutics. Particles also penetrate
through human cystic fibrosis mucus, with >50% delivered particles being
generally diffusive. This approach thus offers a promising means of combatting P. aeruginosa infections, even those
beneath pulmonary mucus, using antivirulence
therapies that do not directly elicit bacterial resistance.

Concept schematic of a mucodiffusive
nanoparticle encapsulating a QS drug that is effective against P. aeruginosa