Repositionable Antibiofilm Drug Candidates, Synergies, and a New Model for Biofilm Formation

Due to the high cost, development time, risk, and low success rate of new antibiotic development programs, the private pharmaceutical industry has withdrawn from antibiotic discovery. Since the early 1980's, the number of new antimicrobials approved by the FDA every year, and hence marketed, has steadily and significantly decreased. Coupled with an increase in drug resistance partially caused by the overuse of common antimicrobials, this drought of new antimicrobials has created an urgent need for novel therapies.

To address this need, a commercially available library of 1,280 chemical compounds was screened for repositionable candidates with activity against planktonic and biofilm Staphylococcus aureus and Pseudomonas aeruginosa. We found that 18 candidate drugs (no previous or limited reports of antimicrobial activity) are effective in killing planktonic (free-floating) Staphylococcus aureus, three of which are effective in disrupting Staphylococcus aureus biofilms. Next, the library was re-screened in combination with Colistin for repositionable synergistic combinations with activity against planktonic and biofilm Pseudomonas aeruginosa. We found seven candidate drug-Colistin combinations that are effective in killing planktonic Pseudomonas aeruginosa, three of which are moderately effective at disrupting Pseudomonas aeruginosa biofilms. Finally, in order to establish a more adequate model of tissue-associated biofilm formation, a new model of was optimized and characterized in a suspended drop platform. We found the optimal growing conditions that yield the most robust biofilm, determined the growth kinetics of representative biofilms, and visualized the growing biofilm using fluorescent and confocal microscopy.