IISc Team Designs Antimicrobial Peptide to Kill Multi-Drug Resistant Bacteria

Researchers at the Indian
Institute of Science (IISc) have designed an antimicrobial peptide (AMP) that
can effectively and quickly kill a notorious multidrug-resistant bacterium
called Acinetobacter baumannii.
This bacterium tops the World
Health Organization’s list of threats that urgently need new antibiotics
because it is remarkably adept at developing drug resistance. It is also one of
six species responsible for most of the infections in hospitals and healthcare
settings.
In a new study published in
Science Advances, IISc researchers used a bioinformatics approach to design a
new short protein (peptide) called Omega76 that can kill A. baumannii by breaking
down its cell membrane. Infected mice treated with Omega76 had much better
survival rates. The team also found that high doses of Omega76 given for
prolonged periods did not produce any toxic effects. Because it is both safe
and effective, it is a promising candidate for developing new antibiotics, the
researchers say.
Antibiotic resistance is a
growing global threat, especially for the hundreds of millions of patients who
develop infections in healthcare settings. A. baumannii is particularly
infamous for its ability to develop resistance very quickly and survive for
long periods in hospitals.
“The significance of A.
baumannii infection was not sufficiently understood earlier…It was regarded as
just another bug in the environment. It has now become a major threat,
especially in the intensive care units,” says Dipshikha Chakravortty, Professor
at the Department of Microbiology and Cell Biology, and one of the senior
authors.
Antibiotics for such infections
may soon become ineffective, as resistance to even last-resort drugs such as
carbapenems is on the rise. They are not entirely safe either; a drug called
colistin, which is considered the last hope for multidrug-resistant infections,
has been found to cause severe kidney damage, says first author and postdoctoral
fellow Deepesh Nagarajan.
Recently, short polypeptides
called antimicrobial peptides (AMPs) that kill bacteria by breaking down their
membranes have shown promise as alternatives to conventional antibiotics.
Standard drugs act by blocking
specific pathways or processes in bacterial cells, but bacteria can evolve to
gain resistance against such drugs. “On the other hand, AMPs actually punch
holes in the bacterial cell membrane. The chances of drug resistance are much
lower because they act by multiple ways and cause actual physical damage,” says
Nagasuma Chandra, Professor at the Department of Biochemistry, and a senior
author.
Collaboration between Chandra’s
computational biology lab and Chakravortty’s microbiology lab was critical for
the interdisciplinary work of designing and testing a new AMP. They turned to
bioinformatics to translate structures of known AMPs into a database of
graphical representations. Then, they wrote an algorithm that would scour this
database, optimize for repeating patterns and properties that bestow greatest
antimicrobial potency, and suggest new structures. Tendency to form helical
structures, for example, was one of the properties the algorithm looked for, as
it would aid in membrane disruption.
The top five peptide structures
suggested by the algorithm were designed and tested in the lab. One of these,
called Omega76, was found to be the most effective at killing A. baumannii,
completely eliminating all bacterial colonies within an hour. When tested in
infected mice, six out of eight treated with Omega76 survived for five days,
while none of the untreated mice did.
The team also found that
Omega76 did not cause any significant damage to normal cells. Its median lethal
dose was higher than colistin and another recently-developed AMP called
pexiganan, indicating that it was safe to use. In mice, multiple high doses of Omega76
could be given over days without causing any significant damage. It could also
be given safely in combination with colistin, the researchers found.
“Our collaboration has really
helped us understand both the design and efficacy of this peptide,” says
Chandra. She and Chakravortty plan to improve its design further, and explore
clinical uses such as treating diabetic wounds and tackling sepsis in hospital
environments.
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