Publication Date:
2020
Description:
〈p〉Publication date: Available online 24 January 2020〈/p〉
〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉
〈p〉Author(s): Julie A. Lawrence, Zhongping Huang, Sivaprakash Rathinavelu, Jin-Feng Hu, Eliane Garo, Michael Ellis, Vanessa L. Norman, Ronald Buckle, Russell B. Williams, Courtney M. Starks, Gary R. Eldridge〈/p〉
〈div xml:lang="en"〉
〈h5〉Abstract〈/h5〉
〈div〉〈p〉Many human diseases, including cystic fibrosis lung infections, are caused or exacerbated by bacterial biofilms. Specialized modes of motility, including swarming and twitching, allow gram-negative bacteria to spread across surfaces and form biofilms. Compounds that inhibit these motilities could slow the spread of biofilms, thereby allowing antibiotics to work better. We previously demonstrated that a set of plant-derived triterpenes, including oleanolic acid and ursolic acid, inhibit formation of 〈em〉E. coli〈/em〉 and 〈em〉Pseudomonas aeruginosa〈/em〉 biofilms, and alter expression of genes involved in chemotaxis and motility. In the present study, we have prepared a series of analogs of oleanolic acid. The analogs were evaluated against clinical isolates of 〈em〉E. coli〈/em〉 and 〈em〉P. aeruginosa〈/em〉 in biofilm formation assays and swarming assays. From these analogs, compound 〈strong〉9〈/strong〉 was selected as a lead compound for further development. Compound 〈strong〉9〈/strong〉 inhibits 〈em〉E. coli〈/em〉 biofilm formation at 4 µg/mL; it also inhibits swarming at ≤ 1 µg/mL across multiple clinical isolates of 〈em〉P. aeruginosa〈/em〉, 〈em〉E. coli〈/em〉, 〈em〉Burkholderia cepacia〈/em〉, and 〈em〉Salmonella enterica〈/em〉, and at 〈 0.5 µg/mL against multiple agricultural strains. Compound 〈strong〉9〈/strong〉 also potentiates the activity of the antibiotics tobramycin and colistin against swarming 〈em〉P. aeruginosa〈/em〉; this is notable, as tobramycin and colistin are inhaled antibiotics commonly used to treat 〈em〉P. aeruginosa〈/em〉 lung infections in people with cystic fibrosis. qPCR experiments suggested that 〈strong〉9〈/strong〉 alters expression of genes involved in regulating Type IV pili; western blots confirmed that expression of Type IV pili components PilA and PilY1 decrease in 〈em〉P. aeruginosa〈/em〉 in the presence of 〈strong〉9〈/strong〉.〈/p〉〈/div〉
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〈div xml:lang="en"〉
〈h5〉Graphical abstract〈/h5〉
〈div〉
〈p〉Many human diseases, including cystic fibrosis lung infections, are caused or exacerbated by bacterial biofilms. Specialized modes of motility, including swarming and twitching, allow gram-negative bacteria to spread across surfaces and form biofilms. Compounds that inhibit these motilities could slow the spread of biofilms, thereby allowing antibiotics to work better. We prepared a series of analogs of oleanolic acid and evaluated them against clinical isolates of 〈em〉E. coli〈/em〉 and 〈em〉P. aeruginosa〈/em〉 in biofilm formation assays and swarming assays. The resulting lead compound inhibits 〈em〉E. coli〈/em〉 biofilm formation at 4 µg/mL; it also inhibits swarming at ≤ 1 µg/mL across multiple clinical isolates of 〈em〉P. aeruginosa〈/em〉, 〈em〉E. coli〈/em〉, 〈em〉Burkholderia cepacia〈/em〉, and 〈em〉Salmonella enterica〈/em〉, and at 〈 0.5 µg/mL against multiple agricultural strains. Compound 〈strong〉9〈/strong〉 also potentiates the activity of the antibiotics tobramycin and colistin against swarming 〈em〉P. aeruginosa〈/em〉; this is notable, as tobramycin and colistin are inhaled antibiotics commonly used to treat 〈em〉P. aeruginosa〈/em〉 lung infections in people with cystic fibrosis.〈/p〉
〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619315007-ga1.jpg" width="267" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉
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Print ISSN:
0968-0896
Electronic ISSN:
1464-3391
Topics:
Chemistry and Pharmacology
,
Medicine
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