TAXIS DRUG CLASS: FtsZ Inhibitors
TITLE: Evaluation of 2,6-difluoro-3-(oxazol-2-ylmethoxy)benzamide chemotypes as Gram-negative FtsZ inhibitors
Publication: NATURE Journal of Antibiotics (online access: https://www.nature.com/articles/s41429-022-00531-9 subscription required)
Publication Date: May 26, 2022
Abstract: FtsZ inhibitors represent a new drug class as no drugs using this mode of action (MOA) have been approved by regulators. 3-alkoxy substituted 2,6-difluorobenzamide scaffold is one of the most studied FtsZ inhibitors among which the most promising anti-MRSA candidate TXA709 is in clinical trials. In this paper, we present the screening and evaluation of a benzamide class that is functionalized at the alkoxy fragment targeting Gram-negative bacteria. The variations in 3-alkoxy substitutions, specifically the hydroxylated alkyl residues to the secondary and stereogenic pseudo-benzylic carbon of their methyleneoxy linker, are particularly active against K. pneumoniae ATCC 10031 in marked contrast to the derivatives related to PC190723, all of which were inactive against Gram-negative bacteria. The two lead molecules TXA6101 and TXY6129 inhibit the polymerization of E. coli FtsZ in a concentration-dependent manner and induce changes in the morphology of E. coli and K. pneumoniae consistent with inhibition of cell division. These classes of compounds, however, were found to be substrates for efflux pumps in Gram-negative bacteria.
WHAT IT MEANS: Our TXA709 oral FtsZ inhibitor targeting gram-positive bacteria, MRSA, is in planning to begin Phase Ib clinical trials. This research paper indicates that our FtsZ Inhibitor could also potentially be used against gram-negative Enterobacteriaceae (a family of 30 different pathogens) if combined with EPIs (efflux pump inhibitors), our other drug class currently under development. This could significantly increase global demand for our drug candidates.
CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator) is a global non-profit partnership dedicated to supporting early development antibacterial R&D to address the rising threat of drug-resistant bacteria. CARB-X is led by Boston University and funding is provided by the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response (ASPR) in the US Department of Health and Human Services; the Wellcome Trust, a global charity based in the UK working to improve health globally; Germany’s Federal Ministry of Education and Research (BMBF); the UK Department of Health and Social Care’s Global Antimicrobial Resistance Innovation Fund (GAMRIF) funded by the UK Government Department of Health and Social Care (DHSC); the Bill & Melinda Gates Foundation, and with in-kind support from National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health (NIH) within the US Department of Health and Human Services. CARB-X is investing up to US$480 million from 2016-2022 to support innovative therapeutics, preventatives and rapid diagnostics. CARB-X funds only projects that target drug-resistant bacteria highlighted on the CDC’s Antibiotic Resistant Threats list, or the Priority Bacterial Pathogens list published by the WHO, with a priority on those pathogens deemed Serious or Urgent on the CDC list or Critical or High on the WHO list. CARB-X is headquartered at Boston University School of Law. https://carb-x.org/. Follow them on Twitter @CARB_X
ABOUT TAXIS PHARMACEUTICALS
TAXIS Pharmaceuticals, Inc. is a clinical stage company developing anti-resistance drug candidates that enable the re-use of the most widely prescribed generic antibiotics against antibiotic-resistant ESKAPE pathogens (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter species). Our TAXISTANCE® anti-resistance drug platform is focused on the disruption of the foundation of bacterial cell wall architecture to address elemental forms of drug resistance. Our most advanced drug candidate, oral TXA709, will be enrolling an additional Phase I human safety clinical trial in healthy volunteers for development as an anti-resistance drug to be used in combination with obsolete antibiotics as a fully oral anti-MRSA treatment. TXA709 targets the Filamenting temperature-sensitive mutant Z (FtsZ) bacterial cell division protein and was granted Qualified Infectious Disease Product (QIDP) designation by the FDA. It may also be possible to develop a FtsZ drug candidate targeting Gram-negative bacteria in the future. Our Efflux Pump Inhibitors (EPIs) represent a new drug class against Gram-negative multidrug-resistant (MDR) pathogens. Bacterial efflux pumps act like bilge pumps by flushing antibiotics out of the bacterial cell and are responsible for antibiotic resistance in many gram-negative strains. TAXIS Pharmaceuticals EPIs have shown that they can resurrect the activity, potency and effectiveness of multiple classes of antibiotics including Macrolides, Cephalosporins, Monobactams, Antimycobacterials, Tetracyclines, Fluoroquinolones and Sulfanomides. Current data reveals synergy with 28 currently approved and marketed antibiotics that no longer work or now require high doses to have any effect.
Gregory G. Mario, CEO
TAXIS Pharmaceuticals, Inc.
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