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Synspira's PAAG Therapy Demonstrates Persistence Against Pseudomonas aeruginosa Persister Cells

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-- Results published in Frontiers in Microbiology-Antimicrobials,
Resistance and Chemotherapy --

Synspira, a privately held company developing a new class of inhaled
glycopolymer-based therapeutics for the treatment of pulmonary disease,
today announced the results of a study exploring the efficacy of
polycationic glycopolymers (complex sugar molecules) as a potential
treatment for recalcitrant pulmonary infections caused by intrinsically
resistant Pseudomonas aeruginosa (P. aeruginosa) persister cells.
The publication, "Novel
glycopolymer eradicates antibiotic- and CCCP- induced persister cells in
Pseudomonas aeruginosa
", was published in Frontiers in
Microbiology-Antimicrobials, Resistance and Chemotherapy.

Antibiotic treatments often fail to completely eradicate a bacterial
infection, leaving behind an antibiotic-tolerant subpopulation of intact
bacterial cells called persisters. Even with high doses of antibiotics,
these dormant bacteria are capable of surviving, which may be an
important factor in the development of antibiotic resistance. Persisters
are considered a major cause for treatment failure and are thought to
greatly contribute to the stubbornness and reoccurrence of chronic
infections.

"There is a need for new target molecules with the ability to safely
address persisters," said Paul Orwin, Ph.D., Professor of Biology at
California State University San Bernardino. "These results provide
evidence that PAAG rapidly permeabilizes and kills P. aeruginosa
persister cells. In the in vitro studies, PAAG demonstrated
bactericical activity against antibiotic and CCCP-induced persister
cells and was able to completely eradicate persisters."

P. aeruginosa is an opportunistic pathogen that often causes
hospital acquired infections in immunocompromised patients and is one of
the primary agents responsible for pulmonary decline and early mortality
in patients with cystic fibrosis (CF). P. aeruginosa infections
in the lungs of CF patients are often comprised of a drug-resistant
subpopulation of persister cells.

The study evaluated the antipersister properties of the polycationic
glycopolymer poly acetyl arginyl glucosamine, or PAAG, being developed
by Synspira as SNSP113, against antibiotic- and carbonyl cyanide
m-chlorophenylhydrazone (CCCP) - induced P. aeruginosa persisters.
PAAG demonstrated greater efficacy against persisters in vitro than
antibiotics currently used to treat persistent chronic infections.

Results of the study showed that PAAG completely eradicated
antibiotic-induced persisters. When exposed to PAAG, antibiotic tolerant P.
aeruginosa
cells demonstrated a 6 to 7-log reduction within two to
four hours and complete eradication within 24 hours of treatment. PAAG
was also explored in the treatment of CCCP-pretreated cultures that were
exposed to different classes of antibiotics with diverse mechanisms of
action such as fluoroquinolones, monobactam (aztreonam), aminoglycoside
(tobramycin), and macrolide (clarithromycin and azithromycin). Exposure
to PAAG resulted in a 4-log reduction of bacteria within one hour of
treatment and complete eradication of CCCP- pretreated P. aeruginosa
cells in 24 hours of treatment. PAAG's anti-persister activity was also
evaluated based on its competence in eliminating persister cells formed
in CCCP pretreated P. aeruginosa cells. PAAG displayed
bactericidal activity against CCCP-induced persister cells of P.
aeruginosa
and achieved complete killing of the initial bacterial
inoculum at concentrations that are not toxic to human cells.

"Antibiotic-induced P. aeruginosa persisters are commonly
implicated in relapsing and chronic lung infections, and increasingly
recognized as culprits that outwit even the most aggressive therapies.
We are optimistic that SNSP113 could provide a fundamentally different
therapy for CF patients with chronic respiratory infections and may play
a significant role in reducing antibiotic resistance," added Shenda
Baker, Ph.D., Chief Executive Officer of Synspira.

About SNSP113
SNSP113 is a glycopolymer-based therapeutic
being developed as an inhaled treatment to improve lung function in
patients with cystic fibrosis. As a modified polysaccharide, SNSP113
interacts with structural polymers in protective bacterial biofilms,
breaking them apart, and with native glycoproteins in mucus, normalizing
mucus viscosity. SNSP113 also interacts with the cell walls of invading
bacteria increasing their permeability, thereby reducing their inherent
viability and potentiating the efficacy of antibiotics. SNSP113 is
designed to reduce infection, airway congestion and inflammation, the
key drivers of pulmonary exacerbations and pulmonary decline in cystic
fibrosis patients.

About Cystic Fibrosis
Cystic fibrosis (CF) is a progressive
genetic disease that causes airway obstruction, persistent lung
infections and chronic inflammation of pulmonary tissue leading to
permanent lung damage and ultimately resulting in respiratory failure.
CF is characterized by the accumulation of thick, sticky mucus in the
lungs and clogged airways which impede breathing. Bacteria are not
easily cleared and create protective biofilms that are difficult for
antibiotics to penetrate and often lead to the emergence of multi-drug
resistant bacteria. More than 30,000 people in the United States, and a
similar number in Europe, live with cystic fibrosis1.

About Synspira
Synspira is developing a new class of inhaled
glycopolymer-based therapeutics to reduce pulmonary inflammation, airway
obstruction and infection, key drivers of pulmonary diseases including
cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and
pneumonia. Synspira has an exclusive license from Synedgen to the
Glycomics Technology Platform for the development of inhaled
therapeutics in pulmonary indications. Synspira is dedicated to
developing drugs with new mechanisms of action to target and change the
course of pulmonary diseases.

1 Cystic Fibrosis Foundation. About Cystic Fibrosis. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/.

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