Development of a Potent and Functional In Vivo Peptide Competitive Inhibitor for the Toxin MazF

TL;DR

Researchers developed a peptide inhibitor called SamF that blocks the bacterial toxin MazF, offering a new way to study and potentially treat bacterial infections.

Contribution

A potent and specific in vivo peptide competitive inhibitor for the toxin MazF was developed.

Findings

SamF tightly and specifically binds to MazF in vitro and in vivo.

Coexpression of SamF with MazF counteracts toxin-induced metabolic downregulation and persister formation.

SamF reveals a new druggable site on MazF for antimicrobial design.

Abstract

Cell growth regulation
granted by toxin–antitoxin systems
enables bacteria to fight phage infections, evade host immune defenses,
and survive antibiotic treatment. In this work, a potent and specific
peptide competitive inhibitor for the Escherichia coli toxin MazF was developed and named Small Antitoxin of MazF (SamF).
Employing a set of N-acetylated and C-amidated synthetic peptides, biophysical methods, biochemistry,
and molecular biology techniques, we demonstrated that SamF binds
tightly and with high specificity to MazF in vitro and in vivo, blocking access to the substrate binding
site. Coexpression of SamF with MazF in E. coli efficiently counteracted the metabolic downregulation imposed by
the toxin and the formation of antibiotic persisters. Altogether,
our data uncovered a new MazF druggable site and an excellent scaffold
for the design of antimicrobials. SamF is also a promising tool to
study MazF in vitro and its physiological function
in bacteria.

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