Our lead clinical candidate, TXA709, is a second-generation prodrug that is metabolized in the body to produce the active agent, TXA707, a benzamide derivative that disrupts the function of FtsZ, a bacterial protein that is essential for bacterial cell division. In the presence of TXA707, FtsZ does not function properly, resulting in bacterial cell death that is achieved more rapidly than that observed with standard antibiotics such as vancomycin. The potent anti-staphylococcal activity of TXA707 is derived from its disruptive actions of the FtsZ protein. The inhibition of FtsZ is considered a novel mechanism of action, allowing the prodrug, TXA709 to overcome common resistance pathways associated with currently marketed antibiotic drugs. In addition, TXA709 shows minimal toxicity against mammalian and human cells, making it an attractive compound for development in the global fight against antibiotic resistance.
Recently published pre-clinical data suggest that TXA709 improves upon earlier-generation FtsZ inhibitors by providing enhanced metabolic stability, improved pharmacokinetic properties, and superior in vivo efficacy against S. aureus isolates that are resistant to current standard-of-care antibiotics, including vancomycin, daptomycin, and linezolid. In an article published in Antimicrobial Agents and Chemotherapy (AAC), researchers reported on a series of challenge studies in which TXA707, the active product of TXA709, exhibited potent bactericidal activity against 66 clinical S. aureus isolates with documented resistance to those standard-of-care drugs.
The AAC publication expanded upon pre-clinical data presented at the April 2015 European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) meeting in Copenhagen, Denmark. In a poster presentation, researchers presented an analysis of antistaphylococcal efficacy in a murine 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 a first-generation TAXIS compound with a similar mechanism of action.
TAXIS is conducting additional research to validate pre-clinical findings and highlight TXA709 as a weapon in the global fight against antibiotic resistance, an area of significant unmet medical need. TAXIS is committed to bringing TXA709, along with other novel, potentially life-saving antibiotic agents, to the clinic.
TAXIS has completed the following pre-clinical studies of TXA709:
|Genotoxicity||No detectable Ames-based mutagenicity|
|Pharmacokinetic (PK) studies in mouse, rat, dog (both intravenous and oral)||Favorable PK parameters observed|
|Metabolites in the presence of mouse and human hepatocytes||Limited Phase I and II metabolism|
|Cytochrome P450 (CYP) inhibition studies (cells transfected with human CYP enzymes)||No significant CYP inhibition|
|CYP induction studies (induction of messenger RNA [mRNA] in human cells)||No significant CYP induction|
|Metabolites (In vivo, mouse urine)||Principal urinary metabolite identified|
|Serum protein binding (mouse, rat, dog, human)||No significant differences between species|
|CYP-phenotype substrate identification (mouse)||CYP3A4, CYP2D2 and CYP2C9 identified|
|Safety study – in vitro pharmacology (Cerep – 44 receptors/channels)||Very few effects, appear to be insignificant|
|Acute and subchronic toxicity with histopathology (mouse, full necropsy and tissue analysis)||No detectable difference between treated and control|
The following TXA709 studies are in progress:
- Synthesis of GMP material
- Process chemistry, stability, salt analyses, and 1.5 kg GMP material
- Salt screens and formulation
- CMO selection process underway
- Comparative analyses of PK for assessment of effective clinical dose range
- Dr. Paul Ambrose, Institute for Clinical Pharmacodynamics, Latham, NY
Other FtsZ Inhibitors
In addition to TXA709, TAXIS is investigating several other FtsZ inhibitors for their activity against various bacterial species with a focus on Gram-negative bacterial infections, which are highly complex and difficult to treat.
FtsZ is an appealing antibacterial target because it is essential for bacterial survival and is conserved across many bacterial species including Gram-positive and Gram-negative species. FtsZ is specific to bacteria, with no functional counterpart in humans. In addition, FtsZ disruption is considered a novel mechanism of action, as it is unexploited by any drug in current clinical use, the majority of which target bacterial cell wall/membrane formation, protein synthesis, or DNA synthesis.
FtsZ-targeting agents appear to disrupt the process by which FtsZ forms a ring-like structure (called the Z-ring) at the middle of the bacterial cell that serves as a scaffold for the recruitment and organization of other critical components of cellular synthesis, septum formation, and cell division. Experiments have shown that TXA707, the active product of the prodrug TXA709, disrupts Z-ring formation in bacteria as well as mislocalization of FtsZ from the septal Z-ring at midcell to distal cellular sites. The mislocalization of septal biosynthesis away from midcell results in disrupted bacterial cell division and, ultimately, cell death.
Based on the demonstrated antibacterial efficacy of TXA709 in vivo and the disruption of bacterial cell division by TXA707, FtsZ appears to be a highly druggable target. As TAXIS continues to investigate this promising class of novel antibiotics, we are confident that the unique mechanism of action of these agents will lead to widespread clinical use once approved.
Gram-Negative Efflux Pump Inhibitors
Efflux, or outward flow, is a process by which foreign substances are moved out of the cell. The process is controlled by transporters called efflux pumps, which are multi-protein complexes that span the bacterial cell membranes. As foreign compounds, such as antibiotics, penetrate the bacterial cell wall, the efflux pumps recognize them and pump them out. As a result, the antibiotics never reach sufficiently high concentrations inside the cell to kill the bacteria, thereby resulting in antibiotic resistance.
The prodrug, TXA709, TAXIS Pharmaceuticals’ lead drug candidate, does not currently target Gram-negative bacterial infections, as the active product TXA707 is a substrate (a molecule upon which an enzyme acts) for an efflux pump commonly associated with Gram-negative bacteria. Blocking the action of that efflux pump should facilitate the accumulation of therapeutic concentrations of TXA707 in the Gram-negative bacterial cell, thereby enabling activity against Gram-negative infections.
TAXIS is therefore applying the Company’s technology and knowledge toward development of efflux pump inhibitors, or EPIs. This area of research involves reactivation of older, generic antibiotic drugs that are no longer effective because the Gram-negative pathogens they target have developed resistance against them due to the acquisition of efflux pumps. Although we are in the early stages of EPI research, in vitro results thus far have been promising, with significant (100- to 1,000-fold) increases in antibiotic potency observed in the Gram-negative pathogens Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.