TAXIS DRUG CLASS: Efflux Pump Inhibitors (EPIs)
TITLE: Evaluation of a Conformationally Constrained Indole Carboxamide as a Potential Efflux Pump Inhibitor in Pseudomonas aeruginosa
Publication: MDPI Journal Antibiotics (online access: https://www.mdpi.com/2079-6382/11/6/716/htm )
Publication Date: May 26, 2022
Abstract: Efflux pumps in Gram-negative bacteria such as Pseudomonas aeruginosa provide intrinsic antimicrobial resistance by facilitating the extrusion of a wide range of antimicrobials. Approaches for combating efflux-mediated multidrug resistance involve, in part, developing indirect antimicrobial agents capable of inhibiting efflux, thus rescuing the activity of antimicrobials previously rendered inactive by efflux. Herein, TXA09155 is presented as a novel efflux pump inhibitor (EPI) formed by conformationally constraining our previously reported EPI TXA01182. TXA09155 demonstrates strong potentiation in combination with multiple antibiotics with efflux liabilities against wild-type and multidrug-resistant (MDR) P. aeruginosa. At 6.25 g/mL, TXA09155, showed >8-fold potentiation of levofloxacin, moxifloxacin, doxycycline, minocycline, cefpirome, chloramphenicol, and cotrimoxazole. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA09155. TXA09155 was determined to lower the frequency of resistance (FoR) to levofloxacin and enhance the killing kinetics of moxifloxacin. Most importantly, TXA09155 outperformed the levofloxacin-potentiation activity of EPIs TXA01182 and MC-04,124 against a CDC/FDA panel of MDR clinical isolates of P. aeruginosa. TXA09155 possesses favorable physiochemical and ADME properties that warrant its optimization and further development.
WHAT IT MEANS: We were able to chemically improve our TXA01182 EPI which resulted in TXA09155, an EPI twice as active in allowing old antibiotics from multiple classes to once again kill antibiotic-resistant P. aeruginosa. Specifically, TXA09155 was successful against 334 strains of MDR (multi-drug-resistant) P. aeruginosa. Finally, TXA09155 showed an overall good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile, suggesting that this new EPI class has the potential to become a successful drug.
ABOUT CARB-X
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.
