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Development of benzo[1,4]oxazines as biofilm inhibitors and dispersal agents against Vibrio cholerae.

Warner CJ, Cheng AT, Yildiz FH, Linington RG - Chem. Commun. (Camb.) (2015)

Bottom Line: Bacterial biofilms are estimated to be associated with over 65 percent of all nosocomial infections.However, no therapeutics have been approved by the FDA which directly mediate biofilm formation or persistence.Herein we report oxazine as a highly potent inhibitor, disperser and in the presence of the appropriate antibiotic eradicator of V. cholerae biofilms.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California Santa Cruz, California, 95064, USA. rliningt@ucsc.edu.

ABSTRACT
Bacterial biofilms are estimated to be associated with over 65 percent of all nosocomial infections. However, no therapeutics have been approved by the FDA which directly mediate biofilm formation or persistence. Herein we report oxazine as a highly potent inhibitor, disperser and in the presence of the appropriate antibiotic eradicator of V. cholerae biofilms.

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Screening of a selection of the oxazine inhibitors against V. cholerae biofilms. A selection of the oxazine derivatives screened as inhibitors of V. cholerae biofilms. BIC50 and BDC50 determined with 3 biological replicates each consisting of two technical replicates, see ESI† for full BIC50 dose response curves and complete list of all compounds screened in the assay.
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fig1: Screening of a selection of the oxazine inhibitors against V. cholerae biofilms. A selection of the oxazine derivatives screened as inhibitors of V. cholerae biofilms. BIC50 and BDC50 determined with 3 biological replicates each consisting of two technical replicates, see ESI† for full BIC50 dose response curves and complete list of all compounds screened in the assay.

Mentions: To identify key elements of the pharmacophore for this compound class, a library of 41 derivatives were prepared using a divergent strategy to diversify both the exocyclic alkene and the methyl ester moiety of the original scaffold (Fig. 1, see ESI† for a comprehensive list of synthesized compounds). Initial examination of the lead compound 1 highlighted the α,β unsaturated carbonyl (C9–C11) as a Michael acceptor with potential involvement in the mechanism of action. In line with the behavior of other Michael acceptors in the literature, modification of the exocyclic methylene unit (compounds 8–12) eliminated activity in all cases.12 Introduction of any substituent onto the double bond (compounds 13–17) also resulted in a pronounced decrease in biofilm inhibition, indicating a tight steric limitation for modifications at this position.


Development of benzo[1,4]oxazines as biofilm inhibitors and dispersal agents against Vibrio cholerae.

Warner CJ, Cheng AT, Yildiz FH, Linington RG - Chem. Commun. (Camb.) (2015)

Screening of a selection of the oxazine inhibitors against V. cholerae biofilms. A selection of the oxazine derivatives screened as inhibitors of V. cholerae biofilms. BIC50 and BDC50 determined with 3 biological replicates each consisting of two technical replicates, see ESI† for full BIC50 dose response curves and complete list of all compounds screened in the assay.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288701&req=5

fig1: Screening of a selection of the oxazine inhibitors against V. cholerae biofilms. A selection of the oxazine derivatives screened as inhibitors of V. cholerae biofilms. BIC50 and BDC50 determined with 3 biological replicates each consisting of two technical replicates, see ESI† for full BIC50 dose response curves and complete list of all compounds screened in the assay.
Mentions: To identify key elements of the pharmacophore for this compound class, a library of 41 derivatives were prepared using a divergent strategy to diversify both the exocyclic alkene and the methyl ester moiety of the original scaffold (Fig. 1, see ESI† for a comprehensive list of synthesized compounds). Initial examination of the lead compound 1 highlighted the α,β unsaturated carbonyl (C9–C11) as a Michael acceptor with potential involvement in the mechanism of action. In line with the behavior of other Michael acceptors in the literature, modification of the exocyclic methylene unit (compounds 8–12) eliminated activity in all cases.12 Introduction of any substituent onto the double bond (compounds 13–17) also resulted in a pronounced decrease in biofilm inhibition, indicating a tight steric limitation for modifications at this position.

Bottom Line: Bacterial biofilms are estimated to be associated with over 65 percent of all nosocomial infections.However, no therapeutics have been approved by the FDA which directly mediate biofilm formation or persistence.Herein we report oxazine as a highly potent inhibitor, disperser and in the presence of the appropriate antibiotic eradicator of V. cholerae biofilms.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California Santa Cruz, California, 95064, USA. rliningt@ucsc.edu.

ABSTRACT
Bacterial biofilms are estimated to be associated with over 65 percent of all nosocomial infections. However, no therapeutics have been approved by the FDA which directly mediate biofilm formation or persistence. Herein we report oxazine as a highly potent inhibitor, disperser and in the presence of the appropriate antibiotic eradicator of V. cholerae biofilms.

Show MeSH
Related in: MedlinePlus