New treatment for drug-resistant bacteria

A molecular model of the F12 biotherapy shows the fold of its polypeptide backbone. Residual T-cell epitopes are mapped onto the structure and colored from white (no epitopes) to dark red (dense overlapping epitopes). The muted red coloring indicates that T-cell epitopes have been broadly silenced in the engineered F12 variant, and this reduced epitope content underlies the molecule’s improved safety and efficacy profile.

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 researchers 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 Dartmouth engineering professor and corresponding author Karl Griswold.

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.

Learn more: Dartmouth-led Team Engineers New Treatment for Drug-Resistant Bacterial Infections

Go deeper with Bing News on:

Drug resistant bacteria

Antibiotic-resistant strains of staph bacteria may be spreading between pigs raised in factory farms
on March 5, 2021 at 11:07 am
DNA sequencing of bacteria found in pigs and humans in rural eastern North Carolina, an area with concentrated industrial-scale pig-farming, suggests that multidrug-resistant Staphylococcus aureus ...
Could this Research Triangle Park company hold a key to fighting drug-resistant bacteria?
on March 5, 2021 at 6:59 am
For generations, antibiotics have been a boon to humanity, saving untold numbers of people from deadly infections and bacteria. But as those antibiotics have been overused across the world — both in ...
Synthesis and design of Ag–Fe bimetallic nanoparticles as antimicrobial synergistic combination therapies against clinically relevant pathogens
on March 5, 2021 at 5:25 am
In recent years, metallo-pharmaceutics and metallic nanoparticles have been proposed as potential alternative antimicrobials due to their broad-spectrum antimicrobial properties. Moreover, recent ...
Why the Meat We Eat Is an Antibiotic-Resistance Threat
on March 2, 2021 at 4:12 pm
Overuse of these medicines in livestock can affect humans, too.
Sen. Cassidy explains why he’s backing a bill aimed at drug-resistant bacteria
on February 26, 2021 at 2:11 am
The senator explains why drug makers have resisted developing new antibiotics, and outlines legislation he believes may help.

Go deeper with Google Headlines on:

Drug resistant bacteria

Tree Resin Compound Defeats Drug-Resistant Bacteria in Lab Tests - Medscape
February 23, 2021
Could this Research Triangle Park company hold a key to fighting drug-resistant bacteria? - Durham Herald Sun
March 5, 2021
Why Sen. Bill Cassidy is backing a bill aimed at drug-resistant bacteria - STAT
February 26, 2021
Antibiotic-resistant strains of staph bacteria may be spreading between pigs raised in factory farms: Findings from DNA-sequencing study raise public health concerns - Science Daily
March 5, 2021
Global travellers vulnerable to drug-resistant bacteria - study - University of Birmingham
February 23, 2021

Go deeper with Bing News on:

F12 lysin-based antibacterial agent

Click-correlative light and electron microscopy (click-AT-CLEM) for imaging and tracking azido-functionalized sphingolipids in bacteria
on February 22, 2021 at 2:28 am
The antimicrobial mechanism, however, remains so far elusive. Here, we introduce ‘click-AT-CLEM’, a labeling technique for correlated light and electron microscopy (CLEM) based on the super ...
A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection
on February 19, 2021 at 9:08 pm
Moreover, prolonged SP 18–28 treatment causes hypersensitivity to DNA-damaging agents and selectively reduces the viability ... “dimer-of-dimers” interface using an innovative peptide-based approach.
Antimicrobial agents and chemotherapy
on February 19, 2021 at 4:00 pm
Efficacy of a Cap-Dependent Endonuclease Inhibitor and Neuraminidase Inhibitors against H7N9 Highly Pathogenic Avian Influenza Virus Causing Severe Viral Pneumonia in Cynomolgus Macaques ...
ContraFect Announces Appointment of Dr. Jane F. Barlow to Board of Directors
on February 11, 2021 at 8:22 am
CFRX), a clinical-stage biotechnology company focused on the discovery and development of direct lytic agents (DLAs) as new medical modalities for the treatment of life-threatening, antibiotic ...
ContraFect Announces Appointment of Dr. Jane F. Barlow to Board of Directors
on February 11, 2021 at 4:12 am
YONKERS, N.Y., Feb. 11, 2021 (GLOBE NEWSWIRE) -- ContraFect Corporation (Nasdaq:CFRX), a clinical-stage biotechnology company focused on the discovery and development of direct lytic agents (DLAs ...