Identification of Novel Cryptic Multifunctional Antimicrobial Peptides from the Human Stomach Enabled by a Computational-Experimental Platform

Autor(es):Mostrar menos -

Pane, Katia ^[1] ; Cafaro, Valeria ^[2] ; Avitabile, Angela ^[2] ; Torres, Marcelo Der Torossian ^{[3, 4, 5, 6, 7, 8, 9]} ; Vollaro, Adriana ^[10] ; De Gregorio, Eliana ^[10] ; Catania, Maria Rosaria ^[10] ; Di Maro, Antimo ^[11] ; Bosso, Andrea ^[2] ; Gallo, Giovanni ^[2] ; Zanfardino, Anna ^[2] ; Varcamonti, Mario ^[2] ; Pizzo, Elio ^[2] ; Di Donato, Alberto ^[2] ; Lu, Timothy K. ^{[3, 4, 6, 7, 8, 9]} ; de la Fuente-Nunez, Cesar ^{[3, 4, 6, 7, 8, 9]} ; Notomista, Eugenio ^[2]

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^[1] IRCCS SDN, Via E Gianturco 113, I-80143 Naples - Italy

^[2] Univ Naples Federico II, Dept Biol, I-80126 Naples - Italy

^[3] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 - USA

^[4] MIT, Elect Res Lab, Cambridge, MA 02139 - USA

^[5] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210580 Santo Andre - Brazil

^[6] MIT, Synthet Biol Grp, Synthet Biol Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[7] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[8] Ctr Microbiome Informat & Therapeut, Cambridge, MA 02139 - USA

^[9] Broad Inst MIT & Harvard, Cambridge, MA 02139 - USA

^[10] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples - Italy

^[11] Univ Naples Federico II, Dept Environm Biol & Pharmaceut Sci & Technol, I-81100 Vanvitelli, Caserta - Italy

• Tipo de documento: Artigo Científico
• Fonte: ACS SYNTHETIC BIOLOGY; v. 7, n. 9, p. 2105-2115, SEP 2018.
• Citações Web of Science: 13

Resumo

Novel approaches are needed to combat antibiotic resistance. Here, we describe a computational-experimental framework for the discovery of novel cryptic antimicrobial peptides (AMPs). The computational platform, based on previously validated antimicrobial scoring functions, indicated the activation peptide of pepsin A, the main human stomach protease, and its N- and C-terminal halves as antimicrobial peptides. The three peptides from pepsinogen A3 isoform were prepared in a recombinant form using a fusion carrier specifically developed to express toxic peptides in Escherichia coli. Recombinant pepsinogen A3-derived peptides proved to be wide-spectrum antimicrobial agents with MIC values in the range 1.56-50 mu M (1.56-12.5 mu M for the whole activation peptide). Moreover, the activation peptide was bactericidal at pH 3.5 for relevant foodborne pathogens, suggesting that this new class of previously unexplored AMPs may contribute to microbial surveillance within the human stomach. The peptides showed no toxicity toward human cells and exhibited anti infective activity in vivo, reducing by up to 4 orders of magnitude the bacterial load in a mouse skin infection model. These peptides thus represent a promising new class of antibiotics. We envision that computationally guided data mining approaches such as the one described here will lead to the discovery of antibiotics from previously unexplored sources. (AU)

• Processo FAPESP: 16/24413-0 - Peptídeos anfipáticos catiônicos antimicrobianos e antibiofilmes
• Beneficiário: Marcelo Der Torossian Torres
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado