Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Abstract

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.

Bismuth nanoparticles obtained by a facile synthesis method exhibit antimicrobial activity againstStaphylococcus aureusandCandida albicans

“…The ability of the BiNPs to inhibit biofilm formation by S. aureus was evaluated following a protocol previously published by our group with minor modifications [34]. Briefly, a “ biofilm broth ” was prepared as follows: 45% Tryptic-Soy Broth (BD Difco, MD), 45 % Brain-Hearth Infusion broth (BD Difco, MD), and 10% Bovine Fetal Serum (BD Difco, MD).…”

Methods Used for the Eradication of Staphylococcal Biofilms

“…Nevertheless, to provide reliable and accurate data, sometimes the analysis of the differences Interestingly, not only resazurin itself, but also several resazurin-based compounds, were used in biofilm examination. One of them, the Presto Blue cell viability reagent (Thermo Fisher Scientific, Waltham, MA, USA), was used in the screening of commercial pharmacologically active small compounds against S. aureus biofilms [90]. However, although RES and XTT both rely on metabolic activity measurements, they were found to not correlate with one another.…”

Innovative approaches to treat Staphylococcus aureus biofilm-related infections

“…Activity against biofilms was reported in 1992, as sub-MIC levels of 5-fluorouracil diminished biofilm formation of S. epidermidis [78,79]. Later, carmofur (1-hexylcarbamoyl-5-fluorouracil) was identified as a hit in the primary screen against planktonic cells of S. aureus and showed antibiofilm activity in a secondary screen [75]. Recently, 5-fluorouracil and 5-fluoro-2'-deoxyfluridine, another fluoropyrimidine, were identified in a screen against planktonic S. aureus USA300 and activity of 5-fluoro-2'-deoxyfluridine was confirmed in a septicemic MRSA mice infection model with concentrations much lower than the concentrations therapeutically used for cancer treatment, and thus with reduced toxicity [80].…”

“…In another comprehensive screening using the same Prestwick Chemical Library, activity was evaluated by measuring inhibition of growth of planktonic S. aureus TCH1516; the screen resulted in the identification of 104 hits, most of them belonging to the group of antimicrobials and antiseptics. However, 18 non-antibiotic drugs were also identified and 9 of these hit compounds were evaluated for activity against S. aureus biofilms [75]. Three of these showed modest activity, including the anthelmintic niclosamide that caused a reduction in the number of culturable S. aureus cells of 1-2 log [75].…”

“…However, 18 non-antibiotic drugs were also identified and 9 of these hit compounds were evaluated for activity against S. aureus biofilms [75]. Three of these showed modest activity, including the anthelmintic niclosamide that caused a reduction in the number of culturable S. aureus cells of 1-2 log [75]. Rajamuthiah et al [76] investigated the activity of niclosamide and another salicylanilide anthelmintic drug, oxyclozanide against planktonic grown ESKAPE pathogens (Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacter species) [76].…”