August 09, 2018
Synspira’s PAAG Therapy Demonstrates Persistence Against Pseudomonas aeruginosa Persister Cells
Cambridge, Mass. – August 9, 2018 – 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 bactericidal 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 glycopolymerpoly 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.
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 fibrosis.
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.
Cystic Fibrosis Foundation. About Cystic Fibrosis. httpss://www.cff.org/What-is-CF/About-Cystic-Fibrosis/.