title: Controlling resistant bacteria with a novel class of β-lactamase inhibitor peptides: from rational design to in vivo analyses.
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.
authors.affiliation: 1] Central Research Facility, Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, WB, India [2].
authors.forename: Santi M
authors.initials: SM
authors.lastname: Mandal
authors.affiliation: 1] Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Centro de Análises, Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brazil [2] Pos-Graducao em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil [3].
authors.forename: Ludovico
authors.initials: L
authors.lastname: Migliolo
authors.affiliation: 1] Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Centro de Análises, Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brazil [2].
authors.forename: Osmar N
authors.initials: ON
authors.lastname: Silva
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Centro de Análises, Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brazil.
authors.forename: Isabel C M
authors.initials: IC
authors.lastname: Fensterseifer
authors.affiliation: Lacen, Laboratório Central de Saúde Publica do Distrito Federal, Brasília, DF, Brazil.
authors.forename: Celio
authors.initials: C
authors.lastname: Faria-Junior
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Centro de Análises, Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brazil.
authors.forename: Simoni C
authors.initials: SC
authors.lastname: Dias
authors.affiliation: Central Research Facility, Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, WB, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Basak
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston; TX 77555, USA.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Hazra
authors.affiliation: 1] Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Centro de Análises, Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brazil [2] Pos-Graducao em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil.
authors.forename: Octávio L
authors.initials: OL
authors.lastname: Franco
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001409:Bacillus cereus / Q000187:drug effects / Q000201:enzymology; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D065093:beta-Lactamase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W128-32
references.pmid: 16844975
references.citation: J Mol Biol. 2011 Mar 11;406(5):730-44
references.pmid: 21238457
references.citation: J Am Chem Soc. 2012 Oct 10;134(40):16798-804
references.pmid: 22974281
references.citation: Nat Med. 2004 Dec;10(12 Suppl):S122-9
references.pmid: 15577930
references.citation: J Mol Biol. 1991 Feb 20;217(4):701-19
references.pmid: 2005620
references.citation: FEBS Lett. 2011 Apr 6;585(7):995-1000
references.pmid: 21402074
references.citation: Blood. 2004 Apr 1;103(7):2827-34
references.pmid: 14645002
references.citation: Antimicrob Agents Chemother. 2012 Jun;56(6):3309-17
references.pmid: 22491685
references.citation: J Med Chem. 2010 Nov 11;53(21):7852-63
references.pmid: 20945905
references.citation: J Comput Chem. 2010 Jan 30;31(2):455-61
references.pmid: 19499576
references.citation: J Med Chem. 2012 Aug 23;55(16):7253-61
references.pmid: 22809409
references.citation: Nature. 2011 Mar 17;471(7338):331-5
references.pmid: 21368759
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17448-53
references.pmid: 23043117
references.citation: Curr Protoc Bioinformatics. 2006 Oct;Chapter 5:Unit-5.6
references.pmid: 18428767
references.citation: N Engl J Med. 2012 Dec 6;367(23):2168-70
references.pmid: 23215553
references.citation: J Bacteriol. 1997 Oct;179(19):6035-40
references.pmid: 9324249
references.citation: Antimicrob Agents Chemother. 2014;58(4):1835-46
references.pmid: 24379206
references.citation: Antimicrob Agents Chemother. 2001 Dec;45(12):3279-86
references.pmid: 11709298
references.citation: Acta Crystallogr D Biol Crystallogr. 2005 Aug;61(Pt 8):1072-9
references.pmid: 16041072
references.citation: J Antimicrob Chemother. 2005 May;55(5):735-41
references.pmid: 15772144
references.citation: J Surg Res. 2012 Aug;176(2):e73-8
references.pmid: 22445457
references.citation: J Phys Chem B. 2010 Sep 9;114(35):11576-83
references.pmid: 20718413
references.citation: J Infect Dis. 2012 Aug 1;206(3):341-51
references.pmid: 22615319
references.citation: J Clin Microbiol. 2013 Jul;51(7):2089-95
references.pmid: 23616448
references.citation: Antimicrob Agents Chemother. 1972 Apr;1(4):283-8
references.pmid: 4208895
references.citation: Biochimie. 2012 Apr;94(4):968-74
references.pmid: 22210491
references.citation: Methods Mol Biol. 1999;112:531-52
references.pmid: 10027275
references.citation: Antimicrob Agents Chemother. 2011 Oct;55(10):4530-6
references.pmid: 21788458
references.citation: PLoS One. 2009;4(4):e5285
references.pmid: 19381271
references.citation: J Biol Chem. 2007 Apr 13;282(15):11291-9
references.pmid: 17287210
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9381-6
references.pmid: 15197262
references.citation: JAMA. 1996 Jan 24-31;275(4):300-4
references.pmid: 8544270
references.citation: PLoS One. 2012;7(8):e39373
references.pmid: 22879874
references.citation: Science. 2012 Nov 30;338(6111):1161-2
references.pmid: 23197523