Encapsulated peptide blocks communication and virulence of resistant Staphylococcus
Antibiotic-resistant hospital pathogens are not to be
underestimated as a health risk. A research team has now introduced a
new approach for treating multiple-drug resistant Staphylococcus in the
journal Angewandte Chemie. It is based on a synthetic peptide
that reduces the virulence of the bacteria by blocking their
communication by “quorum sensing”. Controlled release of the drug from
degradable microparticles very strongly inhibited skin wound infections
in an animal model.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
The hospital is a place where we are supposed to get
healthy, not be made sicker by a dreaded hospital infection. Pathogens
that are often harmless to healthy people can become very dangerous when
they enter the bodies of weakened patients, for example through surgical
wounds or internal examinations. Alarm bells really start to ring in
cases of multidrug resistant bacteria such as methicillin-resistant Staphylococcus
aureus (MRSA), for which almost no antibiotic is effective. In the
USA, about 100,000 hospital infections and almost 20,000 deaths are
attributed to this bacterium.
The more antibiotics, the more resistance. The upcoming
antibiotics crisis can only be overcome through alternative approaches.
“Anti-virulence” strategies thus aim to reduce the infectiousness of the
pathogen without killing it off. This reduces the selective pressure
that leads to the development of resistance. Because the severity of the
infection is reduced, ideally the patient’s immune system can fight off
the infection.
As their point of attack, the interdisciplinary team
working with Helen E. Blackwell at the University of Wisconsin chose a
chemical communication system used by bacteria to communicate with each
other, called quorum sensing (QS). Many bacteria use QS to regulate the
production of virulence factors, or toxins, involved in infections.
Among other things, virulence factors give pathogens the ability to
attach to host cells and enter them.
S. aureus and related
bacteria have a QS circuit based on the “accessory gene regulator” (agr)
system. The QS signal molecule is called the “autoinducing peptide”
(AIP). The research team developed a synthetic peptide similar to AIP
that blocks the agr system with unusual effectiveness, also
blocking QS. Omitting an end part of the peptide chain significantly
slowed the degradation of the inhibitor peptide in tissue. Encapsulation
of the inhibitor in biodegradable polymer particles allowed for delayed
release, prolonging the period of activity—making high effectiveness at
a low dose possible. In a mouse model for skin abscess, infections with S. aureus could be almost completely blocked by a
local injection of the encapsulated peptide.
This new inhibitor peptide could provide an approach to
therapeutic strategies for fighting bacterial infections and may provide
new insights into the role of agr and QS in chronic infections.
In addition, it could be the foundation for the development of coatings
that block bacterial infections for applications like implants.
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About the Author
Dr. Helen Blackwell is the Norman C. Craig Professor and
Associate Chair of Chemistry at the University of Wisconsin-Madison. Her
lab is primairly focused on developing chemical strategies to
interrogate bacterial cell–cell signaling and explore its role in
biologically relevant environments. She works closely with engineers and
clinicians at UW-Madison to apply her team’s chemical probes in
healthcare contexts.