Minor sequence modifications in temporin B cause drastic changes in antibacterial potency and selectivity by fundamentally altering membrane activity

Giorgia Manzo, Philip M. Ferguson, V. Benjamin Gustilo, Charlotte Hind, Melanie Clifford, Tam T. Bui, Alex F. Drake, R. Andrew Atkinson, J. Mark Sutton, Giovanna Batoni, Christian D. Lorenz, David A. Phoenix, A. James Mason*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Antimicrobial peptides (AMPs) are a potential source of new molecules to counter the increase in antimicrobial resistant infections but a better understanding of their properties is required to understand their native function and for effective translation as therapeutics. Details of the mechanism of their interaction with the bacterial plasma membrane are desired since damage or penetration of this structure is considered essential for AMPs activity. Relatively modest modifications to AMPs primary sequence can induce substantial changes in potency and/or spectrum of activity but, hitherto, have not been predicted to substantially alter the mechanism of interaction with the bacterial plasma membrane. Here we use a combination of molecular dynamics simulations, circular dichroism, solid-state NMR and patch clamp to investigate the extent to which temporin B and its analogues can be distinguished both in vitro and in silico on the basis of their interactions with model membranes. Enhancing the hydrophobicity of the N-terminus and cationicity of the C-terminus in temporin B improves its membrane activity and potency against both Gram-negative and Gram-positive bacteria. In contrast, enhancing the cationicity of the N-terminus abrogates its ability to trigger channel conductance and renders it ineffective against Gram-positive bacteria while nevertheless enhancing its potency against Escherichia coli. Our findings suggest even closely related AMPs may target the same bacterium with fundamentally differing mechanisms of action.

Original languageEnglish
Article number1385
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2019

Bibliographical note

Funding Information:
NMR experiments described in this paper were produced using the facilities of the Centre for Biomolecular Spectroscopy, King’s College London, acquired with a Multi-user Equipment Grant from the Wellcome Trust and an Infrastructure Grant from the British Heart Foundation. CDL acknowledges the stimulating research environment provided by the EPSRC Centre for Doctoral Training in Cross-Disciplinary Approaches to NonEquilibrium Systems (CANES, EP/L015854/1). PMF is supported by a Health Schools Studentship funded by the EPSRC.

Funding Information:
NMR experiments described in this paper were produced using the facilities of the Centre for Biomolecular Spectroscopy, King’s College London, acquired with a Multi-user Equipment Grant from the Wellcome Trust and an Infrastructure Grant from the British Heart Foundation. CDL acknowledges the stimulating research environment provided by the EPSRC Centre for Doctoral Training in Cross-Disciplinary Approaches to Non-Equilibrium Systems (CANES, EP/L015854/1). PMF is supported by a Health Schools Studentship funded by the EPSRC.

Publisher Copyright:
© The Author(s) 2019.

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