New treatment for drug-resistant bacterial infections

Date:
September 2, 2020
Source:
Thayer School of Engineering at Dartmouth
Summary:
A new antibacterial agent that has been engineered to essentially
hide from the human immune system may treat life-threatening
MRSA infections.

A new article provides details on the agent, which is the first
lysin- based treatment with the potential to be used multiple
times on a single patient, making it ideal to treat particularly
persistent drug-resistant and drug-sensitive infections.



FULL STORY ==========================================================================
A new antibacterial agent that has been engineered by researchers at
Dartmouth to essentially hide from the human immune system may treat life-threatening MRSA infections. A new paper, published today in
Science Advances, provides details on the agent, which is the first
lysin-based treatment with the potential to be used multiple times
on a single patient, making it ideal to treat particularly persistent drug-resistant and drug-sensitive infections.


==========================================================================
The Centers for Disease Control and Prevention (CDC) has prioritized
finding effective treatment of Methicillin-resistant Staphylococcus aureus (MRSA), one of the most common bacterial pathogens and the single most
deadly drug- resistant bacteria in the United States. Now, a new study
led by Dartmouth Engineering faculty shows promise for an engineered lysin-based antibacterial agent that may enable safe, repeated dosing
to treat life-threatening infections by MRSA and other types of S. aureus.

In recent years, lysins -- enzymes naturally produced by microbes and associated viruses -- have shown potential to treat S. aureus, which
can rapidly acquire resistance to other types of antibiotic drugs.

"Lysins are one of the most promising next-generation antibiotics. They
kill drug-sensitive and drug-resistant bacteria with equal efficacy,
they can potentially suppress new resistance phenotypes, and they also
have this laser- like precision," said Karl Griswold, corresponding
author and associate professor of engineering at Dartmouth.

While there is promise in lysins, development has been slowed due
to concerns that they prompt humans' immune systems to develop
antidrug antibodies, which can have negative side effects including life-threatening hypersensitivity reactions.

That's why the Dartmouth Engineering team -- which also included
researchers in Dartmouth's computer science department, The Lundquist
Institute at Harbor-UCLA Medical Center, Lyticon, and Stealth Biologics -- engineered and patented F12, a new lysin-based antibacterial agent. F12
is essentially able to hide from the human immune system (due to T cell
epitope deletion), and therefore does not cause the same negative side
effects as unmodified, natural lysins.

F12 is the first lysin-based treatment with the potential to be used
multiple times on a single patient, making it ideal to treat particularly persistent drug-resistant and drug-sensitive infections. Preclinical
studies showed the efficacy of F12 does not diminish with repeated doses,
while two other anti- MRSA lysin treatments currently in clinical trials
are only designed to be used a single time.

"We have engineered this super potent, super effective anti-MRSA biotherapeutic, and we've done it in a way that renders it compatible
with and largely invisible to the human immune system. By making it a
safer drug, we've enabled the possibility of dosing multiple times in
order to treat even the most highly refractory infections," said Griswold.

The team's paper, "Globally deimmunized lysostaphin evades human immune surveillance and enables highly efficacious repeat dosing," was published earlier today by Science Advances. The work was the result of two grants
from the National Institutes of Health (NIH) totaling $1.7 million.

The paper details the treatment's positive results in rabbits, mice with partially-humanized immune systems, and studies with extracted human
immune cells. Griswold believes the antibacterial agent could be ready
for human clinical trials as soon as 2023.

"This is the first report of a translation-ready deimmunized lysin,
and F12 has serious, bonafide clinical potential," said Griswold.

Further studies of F12 will examine synergy with standard-of-care
antibacterial chemotherapies; preliminary results suggest the combinations
are extremely potent and suppress drug-resistance phenotypes.


========================================================================== Story Source: Materials provided by
Thayer_School_of_Engineering_at_Dartmouth. Original written by Julie
Bonette. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hongliang Zhao, Seth A. Brooks, Susan Eszterhas, Spencer Heim,
Liang Li,
Yan Q. Xiong, Yongliang Fang, Jack R. Kirsch, Deeptak Verma,
Chris Bailey-Kellogg, and Karl E. Griswold. Globally deimmunized
lysostaphin evades human immune surveillance and enables
highly efficacious repeat dosing. Science Advances, 2020 DOI:
10.1126/sciadv.abb9011 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200902182421.htm

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