NORTH BRUNSWICK, N.J., June 5, 2015 /PRNewswire/ -- TAXIS Pharmaceuticals, a drug-discovery company focused on developing a new class of antibiotic agents to treat life-threatening, multidrug-resistant bacterial infections, today announced the publication of pre-clinical data demonstrating the potential viability of its lead clinical candidate, TXA709, in combating antibiotic resistance. In an article published in Antimicrobial Agents and Chemotherapy (AAC), researchers report that TXA709 improves upon earlier-generation agents from its class by providing enhanced metabolic stability, improved pharmacokinetic properties, and superior in vivo efficacy against Staphylococcus aureus isolates that are resistant to current standard-of-care antibiotics including vancomycin, daptomycin and linezolid.
“The potent anti-staphylococcal activity of TXA709 results from its unique inhibition of FtsZ, a bacterial protein that is essential to bacterial cell division, distinguishing it from other drugs currently in clinical use,” stated lead author Daniel S. Pilch, Ph.D., Associate Professor in the Department of Pharmacology at Rutgers Robert Wood Johnson Medical School, and a co-founder of TAXIS Pharmaceuticals. “In addition, TXA709 shows minimal cytotoxicity against mammalian and human cells, making it an attractive compound for development in the global fight against antibiotic resistance.”
A second-generation FtsZ inhibitor, TXA709 is a prodrug that is metabolized in the body to produce the active agent TXA707, a benzamide derivative that disrupts the function of FtsZ. This disruption results in bacterial cell death that is achieved more rapidly than that observed with standard antibiotics such as vancomycin.
Dr. Pilch and colleagues report on a series of challenge studies in which TXA707 was shown to exhibit potent bactericidal activity against clinical S. aureus isolates with documented resistance to the standard-of-care drugs vancomycin, daptomycin, and linezolid.
TXA707 was shown to have enhanced metabolic stability compared to PC190723, the active product of first-generation prodrugs known as TXY541 and TXY436. As a result of its enhanced stability, TXA707 is associated with improved pharmacokinetic properties in mice compared to PC190723, as evidenced by a 6.5-fold longer half-life (3.65 hours vs. 0.56 hours) and approximately 3-fold greater oral bioavailability (95% vs. 30%). Additionally, the volume of distribution of TXA707 was approximately three times greater than that of normal body water in the mouse, indicating that the compound distributes beyond the vascular space and well into the tissue, where staphylococcal infections often occur. These results were corroborated in a mouse tissue (thigh) model of methicillin-resistant S. aureus (MRSA) infection, in which oral administration of TXA709 was efficacious in treating the infection.
“MRSA commonly infects skin and soft tissue, making it important for antibiotics directed against this pathogen to distribute well into the tissues following oral or intravenous administration,” explained Edmond J. LaVoie, Ph.D., Professor and Chair, Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, co-author of the AAC paper and a co-founder of TAXIS Pharmaceuticals. “The data from the mouse thigh model show that TXA709 is not only orally efficacious in a mouse systemic model of infection, but also in treating MRSA infections of the soft tissue.”
The AAC paper included an analysis of anti-staphylococcal efficacy in a mouse peritonitis model of systemic infection, in which TXA709 was associated with enhanced (two- to four-fold greater) in vivo efficacy against both methicillin-sensitive S. aureus (MSSA) and MRSA strains, compared to TXY541.
Dr. Pilch and colleagues also reported on experiments that validate FtsZ as the bactericidal target of TXA707, which included disruption of FtsZ polymerization dynamics as well as formation of the ring-like structure formed by FtsZ (termed the Z-ring) at the middle of the bacterial cell that is critical for bacterial septum formation and cell division. The mislocalization of septal biosynthetic machinery away from midcell results in disrupted cell division and, ultimately, cell death in S. aureus.
Additionally, TXA709 was found to exhibit minimal toxicity against mammalian and human cells, underscoring the compound’s targeting specificity for bacteria with regard to its mechanism of action.
About TAXIS
TAXIS Pharmaceuticals is a privately held biopharmaceutical company dedicated to developing novel antibiotics to combat the growing threat of multidrug-resistant bacteria. To date, TAXIS has identified and patented twelve (12) new classes of proprietary antibiotic agents that exploit a novel mechanism of bactericidal action distinct from any other antibiotic in clinical use today. The company is currently advancing its lead clinical candidate, TXA709, which is designed to disrupt the division of bacterial cells. The company’s goal is to improve the treatment of multidrug-resistant bacterial infections such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant enterococci (VRE), Clostridium difficile (C-diff), Pseudomonas aeruginosa, and Acinetobacter baumannii.
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SOURCE TAXIS Pharmaceuticals
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