Exploring Inhibition of Bacterial Conjugation Coupling Protein TrwB: Novel Ligands to Fight Antimicrobial Resistance Spread

TL;DR

Scientists found new compounds that can block bacterial conjugation, a key way antibiotic resistance spreads, by targeting a specific protein called TrwB.

Contribution

The study identifies novel small-molecule inhibitors that reduce conjugation frequency by interacting with the TrwB coupling protein.

Findings

A drug repurposing approach identified compounds that reduce R388 plasmid conjugation by 30–40%.

The inhibition is attributed to specific interactions with the TrwB protein.

This strategy offers a potential solution to combat the spread of antimicrobial resistance.

Abstract

Bacterial conjugation is the most sophisticated mechanism
for horizontal
gene transfer. Conjugative plasmids allow the recipient bacterium
to acquire new traits from the donor, such as antimicrobial resistance
(AMR). Among the proteins involved in the plasmid transfer machinery,
the Type IV Coupling Protein (T4CP) links the relaxosome and the Type
IV Secretion System (T4SS). However, despite their biological relevance
and their potential as a target to control AMR, only a few T4CPs have
been exhaustively studied. The archetype of the T4CP family is the
coupling protein of the conjugative plasmid R388, TrwB. The inhibition
of TrwB ATPase activity or oligomerization with small-molecule modulators
is expected to control the transfer of R388, contributing to combat
AMR spread. Following a drug repurposing approach, we have combined
in silico screening studies, molecular dynamics (MD) simulations,
and in vitro bacterial conjugation assays to identify a small collection
of compounds that selectively decrease the frequency of conjugation
of the plasmid R388 (30–40%). Our results suggest that this
inhibition is the result of the specific interaction of these drugs
with TrwB. The search for conjugation inhibitors, via the inactivation
of proteins such as T4CPs, rises as a strategy to advance in solutions
to combat the silent pandemic of AMR.

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