Antimicrobial and Antibiofilm Activities of Helical
Antimicrobial Peptide Sequences Incorporating Metal-Binding Motifs
Posted on 2019-08-25 - 15:13
Antimicrobial peptides (AMPs) represent
alternative strategies
to combat the global health problem of antibiotic resistance. However,
naturally occurring AMPs are generally not sufficiently active for
use as antibiotics. Optimized synthetic versions incorporating additional
design principles are needed. Here, we engineered amino-terminal Cu(II)
and Ni(II) (ATCUN) binding motifs, which can enhance biological function,
into the native sequence of two AMPs, CM15 and citropin1.1. The incorporation
of metal-binding motifs modulated the antimicrobial activity of synthetic
peptides against a panel of carbapenem-resistant enterococci (CRE)
bacteria, including carbapenem-resistant Klebsiella pneumoniae (KpC+) and Escherichia coli (KpC+). Activity modulation
depended on the type of ATCUN variant utilized. Membrane permeability
assays revealed that the in silico selected lead template, CM15, and
its ATCUN analogs increased bacterial cell death. Mass spectrometry,
circular dichroism, and molecular dynamics simulations indicated that
coordinating ATCUN derivatives with Cu(II) ions did not increase the
helical tendencies of the AMPs. CM15 ATCUN variants, when combined
with Meropenem, streptomycin, or chloramphenicol, showed synergistic
effects against E. coli (KpC+ 1812446) biofilms.
Motif addition also reduced the hemolytic activity of the wild-type
AMP and improved the survival rate of mice in a systemic infection
model. The dependence of these bioactivities on the particular amino
acids of the ATCUN motif highlights the possible use of size, charge,
and hydrophobicity to fine-tune AMP biological function. Our data
indicate that incorporating metal-binding motifs into peptide sequences
leads to synthetic variants with modified biological properties. These
principles may be applied to augment the activities of other peptide
sequences.
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Agbale, Caleb
M.; Sarfo, Justice K.; Galyuon, Isaac K.; Juliano, Samuel A.; Silva, Gislaine G. O.; Buccini, Danieli F.; et al. (2019). Antimicrobial and Antibiofilm Activities of Helical
Antimicrobial Peptide Sequences Incorporating Metal-Binding Motifs. ACS Publications. Collection. https://doi.org/10.1021/acs.biochem.9b00440
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AUTHORS (11)
CA
Caleb
M. Agbale
JS
Justice K. Sarfo
IG
Isaac K. Galyuon
SJ
Samuel A. Juliano
GS
Gislaine G. O. Silva
DB
Danieli F. Buccini
MC
Marlon H. Cardoso
MT
Marcelo D. T. Torres
AA
Alfredo M. Angeles-Boza
Cd
Cesar de la Fuente-Nunez
OF
Octavio L. Franco