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Controlling resistant bacteria with a novel class of β-lactamase inhibitor peptides: from rational design to in vivo analyses.

Mandal SM, Migliolo L, Silva ON, Fensterseifer IC, Faria-Junior C, Dias SC, Basak A, Hazra TK, Franco OL - Sci Rep (2014)

Bottom Line: Molecular modeling associated with peptide synthesis improved bactericidal efficacy in addition to amoxicillin, ampicillin and cefotaxime.Moreover, immunological assays were also performed showing that dBLIPs were unable to modify mammalian immune response in both models, reducing the risks of collateral effects.In summary, the unusual peptides here described provide leads to overcome β-lactamase-based resistance, a remarkable clinical challenge.

View Article: PubMed Central - PubMed

Affiliation: 1] Central Research Facility, Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, WB, India [2].

ABSTRACT
Peptide rational design was used here to guide the creation of two novel short β-lactamase inhibitors, here named dBLIP-1 and -2, with length of five amino acid residues. Molecular modeling associated with peptide synthesis improved bactericidal efficacy in addition to amoxicillin, ampicillin and cefotaxime. Docked structures were consistent with calorimetric analyses against bacterial β-lactamases. These two compounds were further tested in mice. Whereas commercial antibiotics alone failed to cure mice infected with Staphylococcus aureus and Escherichia coli expressing β-lactamases, infection was cleared when treated with antibiotics in combination with dBLIPs, clearly suggesting that peptides were able to neutralize bacterial resistance. Moreover, immunological assays were also performed showing that dBLIPs were unable to modify mammalian immune response in both models, reducing the risks of collateral effects. In summary, the unusual peptides here described provide leads to overcome β-lactamase-based resistance, a remarkable clinical challenge.

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Related in: MedlinePlus

dBLIP-1 and dBLIP-2 effects on mice in vivo model against infection of Staphylococcus aureus (top figure) and Escherichia coli (bottom figure).Determination of CFU in S. aureus groups treated with (a) dBLIP 1 and 2, (b) penicillin (PG), (c) ampicillin (AMP) and (d) cefotaxime (CTX). Determination of CFU in E. coli groups treated with (e) dBLIP 1 and 2, (f) penicillin (PG), (g) ampicillin (AMP), (h) and gentamicin (GEM). Bars represent means and SDs from three to six independent experiments. Results are shown as mean ± SD from triplicate measurements. *p, 0.05; **p, 0.01; ***p, 0.001; comparison by ANOVA with Tukey's post hoc test.
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f3: dBLIP-1 and dBLIP-2 effects on mice in vivo model against infection of Staphylococcus aureus (top figure) and Escherichia coli (bottom figure).Determination of CFU in S. aureus groups treated with (a) dBLIP 1 and 2, (b) penicillin (PG), (c) ampicillin (AMP) and (d) cefotaxime (CTX). Determination of CFU in E. coli groups treated with (e) dBLIP 1 and 2, (f) penicillin (PG), (g) ampicillin (AMP), (h) and gentamicin (GEM). Bars represent means and SDs from three to six independent experiments. Results are shown as mean ± SD from triplicate measurements. *p, 0.05; **p, 0.01; ***p, 0.001; comparison by ANOVA with Tukey's post hoc test.

Mentions: Since a considerable reversal of bacterial resistance to β-lactams was observed here for a broad spectrum of clinical isolates and no cytotoxic effect was observed against erythrocytes and macrophages (Table 3), the efficacy of such compounds was investigated in mouse models of bacteremia and sepsis caused by Escherichia coli and also Staphylococcus aureus clinical isolates with high resistance to different antibiotics. In order to determine the in vivo efficacy of dBLIPs in a non-lethal infection by Gram-negative and -positive resistance models (Fig. 3), the CFU in the peritoneal cavity was determined.


Controlling resistant bacteria with a novel class of β-lactamase inhibitor peptides: from rational design to in vivo analyses.

Mandal SM, Migliolo L, Silva ON, Fensterseifer IC, Faria-Junior C, Dias SC, Basak A, Hazra TK, Franco OL - Sci Rep (2014)

dBLIP-1 and dBLIP-2 effects on mice in vivo model against infection of Staphylococcus aureus (top figure) and Escherichia coli (bottom figure).Determination of CFU in S. aureus groups treated with (a) dBLIP 1 and 2, (b) penicillin (PG), (c) ampicillin (AMP) and (d) cefotaxime (CTX). Determination of CFU in E. coli groups treated with (e) dBLIP 1 and 2, (f) penicillin (PG), (g) ampicillin (AMP), (h) and gentamicin (GEM). Bars represent means and SDs from three to six independent experiments. Results are shown as mean ± SD from triplicate measurements. *p, 0.05; **p, 0.01; ***p, 0.001; comparison by ANOVA with Tukey's post hoc test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127500&req=5

f3: dBLIP-1 and dBLIP-2 effects on mice in vivo model against infection of Staphylococcus aureus (top figure) and Escherichia coli (bottom figure).Determination of CFU in S. aureus groups treated with (a) dBLIP 1 and 2, (b) penicillin (PG), (c) ampicillin (AMP) and (d) cefotaxime (CTX). Determination of CFU in E. coli groups treated with (e) dBLIP 1 and 2, (f) penicillin (PG), (g) ampicillin (AMP), (h) and gentamicin (GEM). Bars represent means and SDs from three to six independent experiments. Results are shown as mean ± SD from triplicate measurements. *p, 0.05; **p, 0.01; ***p, 0.001; comparison by ANOVA with Tukey's post hoc test.
Mentions: Since a considerable reversal of bacterial resistance to β-lactams was observed here for a broad spectrum of clinical isolates and no cytotoxic effect was observed against erythrocytes and macrophages (Table 3), the efficacy of such compounds was investigated in mouse models of bacteremia and sepsis caused by Escherichia coli and also Staphylococcus aureus clinical isolates with high resistance to different antibiotics. In order to determine the in vivo efficacy of dBLIPs in a non-lethal infection by Gram-negative and -positive resistance models (Fig. 3), the CFU in the peritoneal cavity was determined.

Bottom Line: Molecular modeling associated with peptide synthesis improved bactericidal efficacy in addition to amoxicillin, ampicillin and cefotaxime.Moreover, immunological assays were also performed showing that dBLIPs were unable to modify mammalian immune response in both models, reducing the risks of collateral effects.In summary, the unusual peptides here described provide leads to overcome β-lactamase-based resistance, a remarkable clinical challenge.

View Article: PubMed Central - PubMed

Affiliation: 1] Central Research Facility, Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, WB, India [2].

ABSTRACT
Peptide rational design was used here to guide the creation of two novel short β-lactamase inhibitors, here named dBLIP-1 and -2, with length of five amino acid residues. Molecular modeling associated with peptide synthesis improved bactericidal efficacy in addition to amoxicillin, ampicillin and cefotaxime. Docked structures were consistent with calorimetric analyses against bacterial β-lactamases. These two compounds were further tested in mice. Whereas commercial antibiotics alone failed to cure mice infected with Staphylococcus aureus and Escherichia coli expressing β-lactamases, infection was cleared when treated with antibiotics in combination with dBLIPs, clearly suggesting that peptides were able to neutralize bacterial resistance. Moreover, immunological assays were also performed showing that dBLIPs were unable to modify mammalian immune response in both models, reducing the risks of collateral effects. In summary, the unusual peptides here described provide leads to overcome β-lactamase-based resistance, a remarkable clinical challenge.

Show MeSH
Related in: MedlinePlus