Journal
BIOPHYSICAL JOURNAL
Volume 102, Issue 5, Pages 1039-1048Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2012.01.048
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Funding
- German Academic Exchange Service
- Italian Ministry of Education, Universities, and Research
- DFG Centre for Functional Nanostructures [TP E1.2]
- Regione Autonoma della Sardegna
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The novel antimicrobial peptide with a dimeric dendrimer scaffold, SB056, was empirically optimized by high-throughput screening. This procedure produced an intriguing primary sequence whose structure-function analysis is described here. The alternating pattern of hydrophilic and hydrophobic amino acids suggests the possibility that SB056 is a membrane-active peptide that forms amphiphilic beta-strands in a lipid environment. Circular dichroism confirmed that the cationic SB056 folds as beta-sheets in the presence of anionic vesicles. Lipid monolayer surface pressure experiments revealed unusual kinetics of monolayer penetration, which suggest lipid-induced aggregation as a membranolytic mechanism. NMR analyses of the linear monomer and the dendrimeric SB056 in water and in 30% trifluoroethanol, on the other hand, yielded essentially unstructured conformations, supporting the excellent solubility and storage properties of this compound. However, simulated annealing showed that many residues lie in the beta-region of the Ramachandran plot, and molecular-dynamics simulations confirmed the propensity of this peptide to fold as a beta-type conformation. The excellent solubility in water and the lipid-induced oligomerization characteristics of this peptide thus shed light on its mechanism of antimicrobial action, which may also be relevant for systems that can form toxic beta-amyloid fibrils when in contact with cellular membranes. Functionally, SB056 showed high activity against Gram-negative bacteria and some limited activity against Gram-positive bacteria. Its potency against Gram-negative strains was comparable (on a molar basis) to that of colistin and polymyxin B, with an even broader spectrum of activity than numerous other reference compounds.
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