A Computationally Designed Peptide Derived from Escherichia coli as a Potential Drug Template for Antibacterial and Antibiofilm Therapies

Author(s):Show less -

Cardoso, Marlon H. ^{[1, 2, 3, 4]} ; Candido, Elizabete S. ^{[2, 3]} ; Chan, Lai Y. ^[4] ; Torres, Marcelo Der Torossian ^{[5, 6, 7, 8, 9, 10]} ; Oshiro, Karen G. N. ^{[1, 3]} ; Rezende, Samilla B. ^[3] ; Porto, William F. ^{[2, 3, 11]} ; Lu, Timothy K. ^{[6, 7, 8, 9, 10]} ; de la Fuente-Nunez, Cesar ^{[6, 7, 8, 9, 10]} ; Craik, David J. ^[4] ; Franco, Octavio L. ^{[1, 2, 3]}

Affiliation:Show less -

^[1] Univ Brasilia, Fac Med, Programa Posgrad Patol Mol, Campus Darcy Ribeiro, Asa Norte, BR-70910900 Brasilia, DF - Brazil

^[2] Univ Catolica Brasilia, Posgrad Ciencias Genom & Biotecnol, Ctr Anal Prote & Bioquim, SGAN 916 Modulo B, Asa Norte, BR-70790160 Brasilia, DF - Brazil

^[3] Univ Catolica Dom Bosco, Programa Posgrad Biotecnol, S Inova Biotech, Ave Tamandare 6000, BR-79117900 Campo Grande, MS - Brazil

^[4] Univ Queensland, Inst Mol Biosci, 306 Carmody Rd, Brisbane, Qld 4072 - Australia

^[5] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP - Brazil

^[6] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 - USA

^[7] MIT, Synthet Biol Ctr, Synthet Biol Grp, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[8] Broad Inst MIT & Harvard, Cambridge, MA 02139 - USA

^[9] MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[10] MIT, Elect Res Lab, Dept Biol Engn, Cambridge, MA 02139 - USA

^[11] Porto Reports, BR-70790160 Brasilia, DF - Brazil

• Document type: Journal article
• Source: ACS INFECTIOUS DISEASES; v. 4, n. 12, p. 1727-1736, DEC 2018.
• Web of Science Citations: 7

Abstract

Computer-aided screening of antimicrobial peptides (AMPs) is a promising approach for discovering novel therapies against multidrug-resistant bacterial infections. Here, we functionally and structurally characterized an Escherichia coli-derived AMP (EcDBS1R5) previously designed through pattern identification {[}alpha-helical set (KK{[}ILV]((3)){[}AILV])], followed by sequence optimization. EcDBS1R5 inhibited the growth of Gram-negative and Gram-positive, susceptible and resistant bacterial strains at low doses (2-32 mu M), with no cytotoxicity observed against non-cancerous and cancerous cell lines in the concentration range analyzed (<100 mu M). Furthermore, EcDBS1R5 (16 mu M) acted on Pseudomonas aeruginosa pre-formed biofilms by compromising the viability of biofilm-constituting cells. The in vivo antibacterial potential of EcDBS1R5 was confirmed as the peptide reduced bacterial counts by two-logs 2 days post-infection using a skin scarification mouse model. Structurally, circular dichroism analysis revealed that EcDBS1R5 is unstructured in hydrophilic environments, but has strong helicity in 2,2,2-trifluoroethanol (TFE)/water mixtures (v/v) and sodium dodecyl sulfate (SDS) micelles. The TFE-induced nuclear magnetic resonance structure of EcDBS1R5 was determined and showed an amphipathic helical segment with flexible termini. Moreover, we observed that the amide protons for residues Met2-Ala8, Arg10, Ala13-A1a16, and Trp19 in EcDBS IRS are protected from the solvent, as their temperature coefficients values are more positive than -4.6 ppb center dot K-1. In summary, this study reports a novel dual-antibacterial/antibiofilm alpha-helical peptide with therapeutic potential in vitro and in vivo against clinically relevant bacterial strains. (AU)

• FAPESP's process: 14/04507-5 - Biological applications of new antimicrobial peptides
• Grantee: Marcelo Der Torossian Torres
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/24413-0 - Antimicrobial and antibiofilm cationic amphipathic peptides
• Grantee: Marcelo Der Torossian Torres
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate