FtsZ

The 'missing link' between bacterial cells and human and plant cells offers key to the process of eukaryogenesis, the point at which animal and plant cells diverge from bacteria. A team of researchers from Nagoya University in Japan may have discovered a missing link between bacterial cells and animal and plant cells, including those of humans. They named it the Odin tubulin. The origin of tubulin is crucial for understanding the process of eukaryogenesis, the point at which animal and plant cells separate from bacteria. In animal and plant cells, tubulin forms microtubules which are critical to their internal organization. Tubulin supports the cell, giving it structure, shape, and internal organization. Because it is so essential to the cell, uncovering the origin of tubulin would be a remarkable step in understanding how the complex cells found in animals and plants diverged from the single cells of bacteria. Archaeons of the Asgard archaea superphylum are crucial to this research because scientists consider them the closest single-celled relative to animal and plant cells. Although these microscopic single-celled organisms look like bacteria, they differ in genetic makeup and cell structure. Therefore, as an intermediary between bacteria and animal/plant cells, scientists regularly use them to understand the evolution of the features of animal/plant cells. In a study published in Science Advances, a group led by Akihiro Narita, Associate Professor of Nagoya University's Division of Biological Science, Graduate School of Science, in collaboration with Tokyo Institute of Technology, Okayama University, and the Earth-Life Science Institute, used x-rays to investigate a tubulin homolog protein from the archaeon Odinarchaeota whose name comes from Odin, a god from Norse mythology. "Its filament structure was surprising. The diameter was 100 nanometers, which is much wider than the microtubules of eukaryotes," Narita explains. "The architecture was also unique. The molecules polymerize into arcs, which are then assembled into a slinky-like coil. We can view this coil structure as an intermediate in the evolution between FtsZ, a bacteria tubulin homologue that also polymerizes into rings, and the tubulin found in plant and animal cells. ' Professor Narita's group has also explained how the tubulin might have evolved. They hypothesize that it emerged before the origin of plant/animal cells. The segregation of chromosomes of increasing size and enlargement of cell size during eukaryogenesis may have required the development of stiffer tubules to navigate the widening cellular distances and/or payloads. This may have produced evolutionary pressure that encouraged a shift from a flexible type to the stiffer parallel protofilament pattern seen in microtubules. Professor Narita is excited about the implications of their discoveries. He says, "We believe it is highly likely that microtubules are the middle of the evolutionary process. This discovery reveals part of how eukaryotes -- including us -- came into being." Funding was provided by JST CREST, Japan (grant number JPMJCR19S5); the Japan Society for the Promotion of Science (grant number JP20H00476); and the Moore-Simons Project on the Origin of the Eukaryotic Cell (grant number GBMF9743), as well as by the ELSI-First Logic Astrobiology Donation Program.

AXIS DRUG CLASS: FtsZ Inhibitors TITLE: Evaluation of 2,6-difluoro-3-(oxazol-2-ylmethoxy)benzamide chemotypes as Gram-negative FtsZ inhibitors Publication: 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. 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. CONTACT Gregory G. Mario, CEO www.taxispharma.com TAXIS Pharmaceuticals, Inc. 9 Deerpark Drive Monmouth Junction, NJ 08852 (732) 230-3074

Highlights: SYDNEY, Australia, June 01, 2021 (GLOBE NEWSWIRE) -- Recce Pharmaceuticals Ltd (ASX:RCE) (FSE:R9Q) (Company), the Company developing new classes of synthetic anti-infectives, is pleased to announce positive results from a pre-clinical study investigating the Mechanism of Action (MoA) of its lead compound RECCE® 327 (R327). R327 is a broad-spectrum synthetic anti-infective that has potential to address the urgent global health threat posed by antibiotic resistant superbugs and emerging viral pathogens. “The data from this study further supports the potential of RECCE® 327 to provide a novel and universal way to treat harmful infections,” said Executive Director & Chief Scientific Officer Michele Dilizia. “We are excited about these highly encouraging results as they provide important insights regarding how RECCE® 327 is able to work repeatedly against the same strain of bacteria and their superbug forms. The study was performed by independent, world leaders in bacterial Mechanism of Action analysis and antibiotic profiling. Key takeaways from this study are as follows: Study 1 – Determination of Minimum Inhibitory Concentration Initial studies were undertaken to determine the MIC of R327 against various test strains of Gram-negative Escherichia coli (E. coli) bacteria in their actively growing (dividing) form to ultimately elucidate R327’s MoA. All conditions started with 1x108 CFU/ml E. coli cells which were then treated with R327 for the indicated period of time. A graphic accompanying this announcement is available at  The bactericidal effect was evident immediately in all tested concentrations. In 5x MIC of R327 ‘crashing’ the ATP viability of bacterial cells in minutes, reportedly faster than any antibiotic tested previously. Study 2 – Efficacy of R327 against actively growing or dividing E. coli Second study determined whether R327 affects the assembly of the bacterial cell division complex. Cell division in bacteria is mediated by the tubulin-like protein FtsZ – a protein essential for cell division (bacteria reproduction) that requires cellular energy. The E. coli clinical isolates were treated to 1x and 5x MIC for 30 minutes and showed 22% (1x MIC) and 17% (5x MIC) of the cells contained FtsZ rings, with the remaining cells containing small FtsZ-GFP filaments, suggesting mid-cell FtsZ rings had disassembled. By 60 minutes, only 17% (1x MIC) and 8% (5x MIC) contained FtsZ rings. The remaining cells displayed small amount of FtsZ-GFP and was completely diffused throughout the cell, indicating a disassembled FtsZ-GFP. These results highlight a decreased occurrence of FtsZ-GFP rings in a concentration dependent manner, concluding that treatment with R327 leads to disassembly of the FtsZ-GFP rings (not allowing bacterial cells to divide, multiply and spread infection). A graphic accompanying this announcement is available at  The image shows treatment of R327 against E. coli at 1x and 5x MIC leading to disassembly of the FtsZ-GFP rings, supporting initial studies which indicated R327 inactivates cellular bioenergetics and is rapidly and irreversibly bactericidal. Graphics accompanying this announcement are available at: Study 3 – Efficacy of R327 against nondividing or stationary-phase E. coli A separate, but related study undertaken was to determine whether R327 is active against nondividing or stationary-phase E. coli using clinical isolate cells. A graphic accompanying this announcement is available at  Current antibiotics rarely retain bactericidal activities against nondividing bacterial cells; however, R327 shows significant activity against both slow-growing bacteria and actively dividing cells, thereby enabling continuous treatment of infections throughout the bacterial cell life cycle. After only 10 minutes of R327 at 1x and 2x MIC, the viable cell counts decreased 100-fold, and after another 30 minutes, cell count decreased further to 10,000-fold (approximately). When exposed to the highest concentration, 5x MIC of R327, viable cell counts decreased 10,000-fold within 10 minutes. In comparison to the positive and negative controls, the report found ampicillin to be nearly completely resistant and ciprofloxacin only having mild activity against the cells. These findings are aimed at elucidating R327’s mechanism of action and will be presented at the World Microbe Forum taking place virtually 20-24 June 2021. Similarly, studies are underway to explore the effect and MoA of R327 on Gram-positive bacteria. About Recce Pharmaceuticals Ltd Recce Pharmaceuticals Ltd (ASX: RCE) is pioneering the development and commercialization of New Classes of Synthetic Anti-Infectives designed to address the urgent global health problems of antibiotic resistant superbugs and emerging viral pathogens. Recce’s anti-infective pipeline is unique and comprised of broad-spectrum synthetic polymer antibiotics RECCE® 327, RECCE® 435, and RECCE® 529 for viral infections with unique mechanisms of action against hyper-mutation on bacteria and viruses, respectively. Patented lead candidate RECCE® 327 has been developed for the treatment of blood infections and sepsis derived from E. coli and S. aureus bacteria – including their superbug forms. Recce’s new antibiotic compound, RECCE® 435, has been formulated for oral use. The FDA has awarded RECCE® 327 Qualified Infectious Disease Product designation under the Generating Antibiotic Initiatives Now (GAIN) Act – labelling it for Fast Track Designation, plus 10 years of market exclusivity post approval. Further to this designation, RECCE® 327 has been included on The Pew Charitable Trusts Global New Antibiotics in Development Pipeline as the only synthetic polymer and sepsis drug candidate in development. Recce wholly owns its automated manufacturing, ready to support first-in-human clinical trials. Recce’s anti- infective pipeline seeks to exploit the unique capabilities of RECCE® technologies targeting synergistic, unmet medical needs. Corporate ContactJames GrahamRecce Pharmaceuticals Ltd+61 (02) 8075 4585James.graham@recce.com.au Media and Investor Relations (AU)Andrew GeddesCityPR+61 (02) 9267 4511ageddes@citypublicrelations.com.au Media and Investor Relations (USA)Jordyn TemperatoLifeSci Communicationsjtemperato@lifescicomms.com