Repository logo
 

An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics.

Published version
Peer-reviewed

Change log

Authors

Cama, Jehangir 
Fletcher, Marcus 
Hammond, Katharine 
Ryadnov, Maxim G 

Abstract

Antimicrobial resistance challenges the ability of modern medicine to contain infections. Given the dire need for new antimicrobials, polypeptide antibiotics hold particular promise. These agents hit multiple targets in bacteria starting with their most exposed regions-their membranes. However, suitable approaches to quantify the efficacy of polypeptide antibiotics at the membrane and cellular level have been lacking. Here, we employ two complementary microfluidic platforms to probe the structure-activity relationships of two experimental series of polypeptide antibiotics. We reveal strong correlations between each peptide's physicochemical activity at the membrane level and biological activity at the cellular level. We achieve this knowledge by assaying the membranolytic activities of the compounds on hundreds of individual giant lipid vesicles, and by quantifying phenotypic responses within clonal bacterial populations with single-cell resolution. Our strategy proved capable of detecting differential responses for peptides with single amino acid substitutions between them, and can accelerate the rational design and development of peptide antimicrobials.

Description

Funder: Winton Programme for the Physics of Sustainability


Funder: Cambridge-NPL studentship


Funder: Trinity-Henry Barlow Scholarship


Funder: Department for Business, Energy and Industrial Strategy, UK Government; doi: http://dx.doi.org/10.13039/100011693

Keywords

Anti-Bacterial Agents, Anti-Infective Agents, Antimicrobial Cationic Peptides, Bacteria, Microfluidics, Structure-Activity Relationship

Journal Title

Sci Rep

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

12

Publisher

Springer Science and Business Media LLC
Sponsorship
European Research Council (647144)
EPSRC (2148169)