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Synthesis and activity of biomimetic biofilm disruptors.

Böttcher T, Kolodkin-Gal I, Kolter R, Losick R, Clardy J - J. Am. Chem. Soc. (2013)

Bottom Line: We used norspermidine, a natural trigger for biofilm disassembly in the developmental cycle of Bacillus subtilis , to develop guanidine and biguanide compounds with up to 20-fold increased potency in preventing biofilm formation and breaking down existing biofilms.These compounds also were active against pathogenic Staphylococcus aureus .An integrated approach involving structure-activity relationships, protonation constants, and crystal structure data on a focused synthetic library revealed that precise spacing of positively charged groups and the total charge at physiological pH distinguish potent biofilm inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.

ABSTRACT
Biofilms are often associated with human bacterial infections, and the natural tolerance of biofilms to antibiotics challenges treatment. Compounds with antibiofilm activity could become useful adjuncts to antibiotic therapy. We used norspermidine, a natural trigger for biofilm disassembly in the developmental cycle of Bacillus subtilis , to develop guanidine and biguanide compounds with up to 20-fold increased potency in preventing biofilm formation and breaking down existing biofilms. These compounds also were active against pathogenic Staphylococcus aureus . An integrated approach involving structure-activity relationships, protonation constants, and crystal structure data on a focused synthetic library revealed that precise spacing of positively charged groups and the total charge at physiological pH distinguish potent biofilm inhibitors.

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Related in: MedlinePlus

Stagesin the developmental cycle of biofilm formation and disruption.Norspermidine both prevents the formation of new biofilms and collapsesthe structure of existing biofilms.
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fig1: Stagesin the developmental cycle of biofilm formation and disruption.Norspermidine both prevents the formation of new biofilms and collapsesthe structure of existing biofilms.

Mentions: In response to this challenge,high-throughput assays have beendeveloped to identify small molecules with the ability to preventbiofilm formation or disrupt existing biofilms.8 We recently explored an alternative strategy that exploitsthe normal developmental cycle of bacteria. Biofilms form when planktonicbacteria in the aqueous phase aggregate on a solid surface or at anair–liquid interface. The biofilm colony grows both by recruitmentand cell division to form a mature colony. Mature colonies eventuallydisintegrate, and the dispersed bacteria resume a planktonic lifestyle(Figure 1). Bacterially produced small moleculesorchestrate the creation and disintegration of biofilms, and identifyingthese molecular signals could lead to therapeutically useful templates.


Synthesis and activity of biomimetic biofilm disruptors.

Böttcher T, Kolodkin-Gal I, Kolter R, Losick R, Clardy J - J. Am. Chem. Soc. (2013)

Stagesin the developmental cycle of biofilm formation and disruption.Norspermidine both prevents the formation of new biofilms and collapsesthe structure of existing biofilms.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585461&req=5

fig1: Stagesin the developmental cycle of biofilm formation and disruption.Norspermidine both prevents the formation of new biofilms and collapsesthe structure of existing biofilms.
Mentions: In response to this challenge,high-throughput assays have beendeveloped to identify small molecules with the ability to preventbiofilm formation or disrupt existing biofilms.8 We recently explored an alternative strategy that exploitsthe normal developmental cycle of bacteria. Biofilms form when planktonicbacteria in the aqueous phase aggregate on a solid surface or at anair–liquid interface. The biofilm colony grows both by recruitmentand cell division to form a mature colony. Mature colonies eventuallydisintegrate, and the dispersed bacteria resume a planktonic lifestyle(Figure 1). Bacterially produced small moleculesorchestrate the creation and disintegration of biofilms, and identifyingthese molecular signals could lead to therapeutically useful templates.

Bottom Line: We used norspermidine, a natural trigger for biofilm disassembly in the developmental cycle of Bacillus subtilis , to develop guanidine and biguanide compounds with up to 20-fold increased potency in preventing biofilm formation and breaking down existing biofilms.These compounds also were active against pathogenic Staphylococcus aureus .An integrated approach involving structure-activity relationships, protonation constants, and crystal structure data on a focused synthetic library revealed that precise spacing of positively charged groups and the total charge at physiological pH distinguish potent biofilm inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.

ABSTRACT
Biofilms are often associated with human bacterial infections, and the natural tolerance of biofilms to antibiotics challenges treatment. Compounds with antibiofilm activity could become useful adjuncts to antibiotic therapy. We used norspermidine, a natural trigger for biofilm disassembly in the developmental cycle of Bacillus subtilis , to develop guanidine and biguanide compounds with up to 20-fold increased potency in preventing biofilm formation and breaking down existing biofilms. These compounds also were active against pathogenic Staphylococcus aureus . An integrated approach involving structure-activity relationships, protonation constants, and crystal structure data on a focused synthetic library revealed that precise spacing of positively charged groups and the total charge at physiological pH distinguish potent biofilm inhibitors.

Show MeSH
Related in: MedlinePlus