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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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Protonation and charge states. (A) Average degree of protonationof polyamines and corresponding di- or triguanidines as a functionof pH. (B) Classical, incorrect representation of protonated biguanides.(C) Correct protonation state for 11. (D) Biguanide moietycropped from the crystal structure of 11.
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fig4: Protonation and charge states. (A) Average degree of protonationof polyamines and corresponding di- or triguanidines as a functionof pH. (B) Classical, incorrect representation of protonated biguanides.(C) Correct protonation state for 11. (D) Biguanide moietycropped from the crystal structure of 11.

Mentions: Speciation data derived from the pKa values were generated using the program HySS (Figures S12–S14), and the average chargewas plottedagainst pH for each molecule (Figure 4). Forconvenience, protonation states will be given by a string of digits,with 1 for a protonated site and 0 for a nonprotonated site. In thisnotation, the fully protonated state of norspermidine is denoted as(111). Diethylenetriamine(DET) has one extremely low protonation constant of 3.9 that resultsin one amino group being uncharged [protonation state (101)] in thewide pH range of 5–8 (Figure 4A). Althoughguanidine groups in the related structure 2 significantlyincrease the third pKa value to 6.3, thecentral amino group remains unprotonated at physiological pH (101),as confirmed by X-ray structure analysis (FigureS17).


Synthesis and activity of biomimetic biofilm disruptors.

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

Protonation and charge states. (A) Average degree of protonationof polyamines and corresponding di- or triguanidines as a functionof pH. (B) Classical, incorrect representation of protonated biguanides.(C) Correct protonation state for 11. (D) Biguanide moietycropped from the crystal structure of 11.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Protonation and charge states. (A) Average degree of protonationof polyamines and corresponding di- or triguanidines as a functionof pH. (B) Classical, incorrect representation of protonated biguanides.(C) Correct protonation state for 11. (D) Biguanide moietycropped from the crystal structure of 11.
Mentions: Speciation data derived from the pKa values were generated using the program HySS (Figures S12–S14), and the average chargewas plottedagainst pH for each molecule (Figure 4). Forconvenience, protonation states will be given by a string of digits,with 1 for a protonated site and 0 for a nonprotonated site. In thisnotation, the fully protonated state of norspermidine is denoted as(111). Diethylenetriamine(DET) has one extremely low protonation constant of 3.9 that resultsin one amino group being uncharged [protonation state (101)] in thewide pH range of 5–8 (Figure 4A). Althoughguanidine groups in the related structure 2 significantlyincrease the third pKa value to 6.3, thecentral amino group remains unprotonated at physiological pH (101),as confirmed by X-ray structure analysis (FigureS17).

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