Fluorous lipopetides act as highly effective antibiotics
Multidrug-resistant bacterial infections that cannot be
treated by any known antibiotics pose a serious global threat. In the
journal Angewandte Chemie, a Chinese research team has now
introduced a method for the development of novel antibiotics to fight
resistant pathogens. The drugs are based on protein building blocks with
fluorous lipid chains.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Antibiotics are often prescribed far too readily. In many
countries they are distributed without prescriptions and administered in
factory farming: prophylactically to prevent infections and enhance
performance. As a result, resistance is on the rise—increasingly against
reserve antibiotics as well. The development of innovative alternatives
is essential.
It is possible to learn some lessons from the microbes
themselves. Lipoproteins, small protein molecules with fatty acid
chains, are widely used by bacteria in their battles against microbial
competitors. A number of lipoproteins have already been approved for use
as drugs. The common factors among the active lipoproteins include a
positive charge and an amphiphilic structure, meaning they have segments
that repel fat and others that repel water. This allows them to bind to
bacterial membranes and pierce through them to the interior.
A team led by Yiyun Cheng at East China Normal University
in Shanghai aims to amplify this effect by replacing hydrogen atoms in
the lipid chain with fluorine atoms. These make the lipid chain
simultaneously water-repellant (hydrophobic) and fat-repellant
(lipophobic). Their particularly low surface energy strengthens their
binding to cell membranes while their lipophobicity disrupts the
cohesion of the membrane.
The team synthesized a spectrum (substance library) of
fluorous lipopeptides from fluorinated hydrocarbons and peptide chains.
To link the two pieces, they used the amino acid cysteine, which binds
them together via a disulfide bridge. The researchers screened the
molecules by testing their activity against methicillin-resistant Staphylococcus
aureus (MRSA), a widespread, highly dangerous strain of bacteria
that is resistant to nearly all antibiotics. The most effective compound
they found was “R6F”, a fluorous lipopeptide made of six arginine units
and a lipid chain made of eight carbon and thirteen fluorine atoms. To
increase biocompatibility, the R6F was enclosed within phospholipid
nanoparticles.
In mouse models, R6F nanoparticles were shown to be very
effective against sepsis and chronic wound infections by MRSA. No toxic
side effects were observed. The nanoparticles seem to attack the
bacteria in several ways: they inhibit the synthesis of important
cell-wall components, promoting collapse of the walls; they also pierce
the cell membrane and destabilize it; disrupt the respiratory chain and
metabolism; and increase oxidative stress while simultaneously
disrupting the antioxidant defense system of the bacteria. In
combination, these effects kill the bacteria—other bacteria as well as
MRSA. No resistance appears to develop.
These insights provide starting points for the development
of highly efficient fluorous peptide drugs to treat multi-drug resistant
bacteria.
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About the Author
Dr. Yiyun Cheng is Professor of Materials Chemistry and Biotechnology at
the School of Life Sciences, East China Normal University. His research
interests focus on the rational design of biomaterials for cytosolic
delivery of biomacromolecules such as DNA, RNA, protein and peptide.
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