6CT4

TFE-induced NMR structure of an antimicrobial peptide (EcDBS1R5) derived from a mercury transporter protein (MerP - Escherichia coli)

Summary for 6CT4

• Entry DOI: 10.2210/pdb6ct4/pdb
• NMR Information: BMRB: 30442
• Descriptor: EcDBS1R5 (1 entity in total)
• Functional Keywords: antimicrobial peptide, antibiotics, bacterial resistance, drug design, antimicrobial protein
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 2152.79

Authors

Cardoso, M.H.,Chan, L.Y.,Candido, E.S.,Craik, D.J.,Franco, O.L. (deposition date: 2018-03-22, release date: 2018-11-14, Last modification date: 2024-05-01)

Primary citation

Cardoso, M.H.,Candido, E.S.,Chan, L.Y.,Der Torossian Torres, M.,Oshiro, K.G.N.,Rezende, S.B.,Porto, W.F.,Lu, T.K.,de la Fuente-Nunez, C.,Craik, D.J.,Franco, O.L.
A Computationally Designed Peptide Derived from Escherichia coli as a Potential Drug Template for Antibacterial and Antibiofilm Therapies.
ACS Infect Dis, 4:1727-1736, 2018

PubMed 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 [α-helical set (KK[ILV][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 μM), with no cytotoxicity observed against non-cancerous and cancerous cell lines in the concentration range analyzed (<100 μM). Furthermore, EcDBS1R5 (16 μM) 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-Ala16, and Trp19 in EcDBS1R5 are protected from the solvent, as their temperature coefficients values are more positive than -4.6 ppb·K. In summary, this study reports a novel dual-antibacterial/antibiofilm α-helical peptide with therapeutic potential in vitro and in vivo against clinically relevant bacterial strains.

PubMed: 30346140
DOI: 10.1021/acsinfecdis.8b00219

Experimental method

SOLUTION NMR