A Novel Combination Therapy to Treat Biofilm-based Pneumonia Infections

Abstract
Bronchiectasis is a lung pathology characterized by a permanent dilation of the bronchi and is associated with a
chronic cough, sputum production and recurrent respiratory infections. Cystic fibrosis (CF) is one of the best
understood inherited conditions that leads to progressive bronchiectasis, chronic bacterial infection and
premature mortality. Both non-CF bronchiectasis (NCFB) and CF have increased in prevalence and present a
significant burden on healthcare systems worldwide, with an estimated prevalence of NCFB of about 213 cases
per 100,000 persons. These data suggest that between 340,000 and 522,000 adults were receiving treatment
for NCFB in 2013 and that 70,000 adults were newly diagnosed that year. CF, affects 70,000 people worldwide.
Both CF and NCFB are associated with bacterial biofilms, which are difficult to clear with standard antibiotics as
bacteria residing in a biofilm have increased basal resistance or tolerance to antibiotics, often at 1000X the level
of their planktonic counterparts. Therefore, many biofilm-based infections, such as CF and NCFB, are never
cleared by antibiotic therapy, and chronic infections are now recognized as a biofilm-based disease. Developing
new therapeutic interventions that potentiate the ability of antibiotics to sterilize biofilms would be highly
significant in the clinic to prevent and resolve these infections.
This Phase I SBIR proposes experiments to further develop a novel antimicrobial combination therapeutic for
the treatment of CF and NCFB by pulmonary delivery. We previously designed and carried out a high-throughput
screen to identify small molecules that enhances tobramycin killing of P. aeruginosa biofilms. This screen led us
to discover that the commonly used antimicrobial agent triclosan, when combined with tobramycin, increases
biofilm eradication by over 100-fold compared to either treatment alone. This combination also shows activity
against Gram-positive biofilm formers. Based on the extensive safety studies of triclosan and an acceptable
safety profile, this combination, delivered directly to the lung, has significant clinical potential. Our team of the
Waters laboratory at Michigan State University and the TSRL Preclinical Accelerator brings together diverse
expertise in biofilm formation, animal models of efficacy, PK/PD studies, and product development to perform
the pre-clinical studies necessary to initiate a pre-IND meeting with the FDA.Project Narrative
TSRL and its collaborators at Michigan State University are developing a novel combination antibiotic drug
product for the treatment of, initially, bacterial infections in cystic fibrosis and non-cystic fibrosis bronchiectasis
patients. The proposed research will establish the proof-of-concept that effective treatment of pulmonary
bacterial infections can be achieved with this novel combination product, without rendering significant treatment
limiting toxic effects.