TAXIS Pharmaceuticals is developing novel classes of antibiotics to address the growing threat of multidrug-resistant bacteria. Our researchers have the capability to synthesize new compounds, evaluate their antibacterial and targeting activities, conduct pre-clinical studies, and optimize formulations. Our liquid chromatography-mass spectrometry (LCMS) technology enhances our ability to rapidly characterize newly synthesized compounds in real time, significantly enhancing our discovery chemistry throughput.
TAXIS’ lead product candidate, TXA709, is poised to enter the clinic, signaling our transition into a development-stage drug-discovery company. Our ongoing research efforts are focused on disrupting the foundation of bacterial cell wall architecture – including construction, maintenance, and growth – to address elemental drug resistance mechanisms.
Efflux Pump Inhibition
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.
TAXIS has filed 13 patents arising from our EPI drug discovery program. Since the program’s initiation in 2014, the Company has identified seven viable EPI candidate compounds, and expects to identify clinical candidates by the end of 2017. The platform, which includes pathogen-specific as well as broad-spectrum EPI candidates, appears to impact a wide range of antibiotic classes, including macrolides, cephalosporins, monobactams, sulfanomides, tetracyclines, and fluoroquinolones. TAXIS’ investigational EPIs have exhibited potent synergy with 19 antibiotics thus far. The Company is developing pathogen-specific EPI candidates that target Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter Baumannii, and Eschericchia coli species; one of these candidates, TXY9155, has demonstrated durable, validated in vivo efficacy in combination with a cephalosporin in a murine septicemia model of P. aeruginosa infection, and appears to potentiate multiple classes of antibiotics against this bacterial species.
To fuel the continued growth of the EPI drug discovery program, TAXIS has prioritized the generation of new drug candidates and the optimization of existing candidates. The Company is collaborating with leading experts in the field to enhance our understanding of the mechanism of synergistic activity between our EPI candidates and existing antibiotics, and seeks to extend the validated in vivo efficacy of our candidates to a broader spectrum of Gram-negative bacteria. These avenues of research are designed to expand TAXIS’ portfolio of synergistic antibiotics. Our initial focus is on resuscitating the activity of several generic antibiotics, a development that may facilitate access to inexpensive, life-saving medications in community settings across the globe. Our synergistic EPI candidates may similarly revive the commercial prospects of a host of branded antibiotics, enabling the re-introduction of these agents as EPI-based combination products, thereby extending their product lifecycles. Additionally, our synergistic EPI candidates can facilitate research and development efforts by enabling significantly lower antibiotic doses to achieve a therapeutic effect, thereby addressing the problem of dose-related toxicity.
TAXIS has an early-stage drug discovery program that focuses on modulation of MreB, a bacterial protein that controls the shape of rod-shaped bacteria such as Escherichia coli. Inhibition of MreB appears to undermine bacterial cell shape integrity, polar protein localization and/or chromosome segregation, presenting a potentially large market opportunity for antibiotic agents with this novel mechanism of action.
Clinical Research Partnerships
TAXIS partners with contract manufacturing organizations and contract research organizations to plan and implement clinical development programs. These steps include: initiating Good Manufacturing Practice (GMP) scale-up, maintaining Good Laboratory Practice (GLP), and preparing studies to enable Investigational New Drug (IND) applications for our lead product candidates.