It is now well established that bacterial infections are often associated with biofilm phenotypes that demonstrate increased resistance to common antimicrobials. Further, due to the collective attrition of new antibiotic development programs by the pharmaceutical industries, drug repurposing is an attractive alternative. In this work, we screened 1,280 existing commercially available drugs in the Prestwick Chemical Library, some with previously unknown antimicrobial activity, against Staphylococcus aureus, one of the commonly encountered causative pathogens of burn and wound infections. From the primary screen of the entire Prestwick Chemical Library at a fixed concentration of 10 M, 104 drugs were found to be effective against planktonic S. aureus strains, and not surprisingly, these were mostly antimicrobials and antiseptics. The activity of 18 selected repurposing candidates, that is, drugs that show antimicrobial activity that are not already considered antimicrobials, observed in the primary screen was confirmed in dose-response experiments. Finally, a subset of nine of these drug candidates was tested against preformed biofilms of S. aureus. We found that three of these drugs, niclosamide, carmofur, and auranofin, possessed antimicrobial activity against preformed biofilms, making them attractive candidates for repurposing as novel antibiofilm therapies.

Polymer-based platforms in drug-eluting stents ͑DESs͒ can cause adverse reactions in patients. Hence, the development of a polymer-free drug delivery platform may reduce adverse reactions to DES. In this study, the use of a polymer-free platform, self-assembled monolayers ͑SAMs͒, is explored for delivering an antiproliferative drug ͓paclitaxel ͑PAT͔͒ from a stent material ͓cobalt-chromium ͑͑Cou Cr͒ alloy͔. Initially, carboxylic acid terminated phosphonic acid SAMs were coated on Cou Cr alloy. Two different doses ͑25 and 100 g / cm 2 ͒ of PAT were coated on SAM coated Cou Cr surfaces using a microdrop deposition method. Also, control experiments were carried out to coat PAT directly on Cou Cr surfaces with no SAM modification. The PAT coated specimens were characterized using the Fourier transform infrared spectroscopy ͑FTIR͒, scanning electron microscopy ͑SEM͒, and atomic force microscopy ͑AFM͒. FTIR spectra showed the successful deposition of PAT on SAM coated and control-Cou Cr surfaces. SEM images showed islands of high density PAT crystals on SAM coated surfaces, while low density PAT crystals were observed on control-Cou Cr alloy. AFM images showed molecular distribution of PAT on SAM coated as well as control-Cou Cr alloy surfaces. In vitro drug release studies showed that PAT was released from SAM coated Cou Cr surfaces in a biphasic manner ͑an initial burst release in first 7 days was followed by a slow release for up to 35 days͒, while the PAT was burst released from control-Cou Cr surfaces within 1-3 days. Thus, this study demonstrated the use of SAMs for delivering PAT from Cou Cr alloy surfaces for potential use in drug-eluting stents.

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Biofilm-associated Pseudomonas aeruginosa infections remain a significant clinical challenge since the conventional antibiotic treatment or combination therapies are largely ineffective; and new approaches are needed. To circumvent the major challenges associated with discovery of new antimicrobials, we have screened a library of compounds that are commercially available and approved by the FDA (Prestwick Chemical Library) against P. aeruginosa for effective antimicrobial and anti-biofilm activity. A preliminary screen of the Prestwick Chemical Library alone did not yield any repositionable candidates, but in a screen of combinations with a fixed sub-inhibitory concentration of the antibiotic colistin we observed 10 drugs whose bacterial inhibiting activity was reproducibly enhanced, seven of which were enhanced by more than 50%. We performed checkerboard assays of these seven drugs in combination with colistin against planktonic cells, and analysis of their interactions over the complete combination matrix using the Zero Interaction Potency (ZIP) model revealed interactions that varied from highly synergistic to completely antagonistic. Of these, five combinations that showed synergism were down-selected and tested against preformed biofilms of P. aeruginosa. Two of the five combinations were active against preformed biofilms of both laboratory and clinical strain of P. aeruginosa, resulting in a 2-log reduction in culturable cells. In summary, we have identified synergistic combinations of five commercially available, FDA-approved drugs and colistin that show antimicrobial activity against planktonic P. aeruginosa (Clomiphene Citrate, Mitoxantrone Dihydrochloride, Methyl Benzethonium Chloride, Benzethonium Chloride, and Auranofin) as well as two combinations (Auranofin and Clomiphene Citrate) with colistin that show antibiofilm activity.