Novel Antibiofilm Treatments for Pseudomonas aeruginosa Infection - Abstract/Project Summary
The CDC reported that in 2019, 2.8 million infections due to antibiotic resistant bacteria occurred in the US,
causing over 35,000 deaths. Bacterial biofilms are responsible for many of these infections, as biofilms
confer resistance to multiple antibiotics via nonspecific factors such as exclusion of the drug and altered
bacterial metabolism. Multidrug resistant Pseudomonas aeruginosa, a strong biofilm-forming pathogen, was
responsible for 32,000 infections and 2,700 deaths in 2019. Most of these infections are associated with
biofilms, and P. aeruginosa displays the nonspecific antibiotic resistance conferred by the complex biofilm
it forms. To combat the increasing threat of this pathogen innovative intervention strategies must be
designed. One of these strategies is synergy with currently used antibiotics. We employ high throughput
screens (HTS) of chemical libraries and screening of complex plat products to identify synergistic
compounds and substances that effectively eradicate preformed biofilms. A multistep HTS of over 6,000
synthetic compounds identified two promising candidates, triclosan (TRI) and oxyclozanide (OXY), that
synergize with the antibiotic tobramycin (TOB) against established P. aeruginosa biofilms. Triclosan is a
well-studied antimicrobial approved by the FDA. However it has not been studied for synergy with TOB. In
addition, a screen of plant-derived substances identified Larrea tridentata and a component of Hydrastis
canadensis as capable of eradicating preformed P. aeruginosa biofilms. Berberine (BER), a compound
made by Hydrastis, inhibited P. aeruginosa biofilms in our assays and has previously been shown to
synergize with TOB. We propose to test this synergy in a biofilm wound infection model, which has not been
done. We have now shown that extracts of Larrea, which is also known as Creosote (CRE), are highly
active against established P. aeruginosa biofilms, and we have shown this extract to be effective in a murine
biofilm wound model of P. aeruginosa infection. This model is based on in vivo bioluminescence imaging
(BLI), which greatly speeds the process of in vivo testing of biofilm infection in animals. Bioluminescent P.
aeruginosa form a biofilm on the underside of a scab over the wound, allowing quantification of the infection
in individual animals over time by non-invasive imaging. Here, we propose to develop the treatments we
have identified by testing TOB synergy of the compounds and extracts in the BLI wound model. This
process will establish novel treatments for P. aeruginosa biofilm infections in a rapid and quantitative manner.