FtsZ inhibitors represent a new drug class as no drugs using this mode of action (MOA) have been approved by regulators. In this paper, we present the screening and evaluation of a benzamide class that is functionalized at the alkoxy fragment targeting Gram-negative bacteria.
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.
Efflux Pump Inhibitor (EPI) drug candidates appears in the August 13th special Antibiotic Alternatives issue of ACS Infectious Diseases. The paper titled “The CARB-X Portfolio of Nontraditional Antibacterial Products”
On April 15, 2021, the World Health Organization (WHO) released their report titled “2020 Antibacterial Agents in Clinical and Preclinical Development” naming TAXIS Pharmaceuticals’ FtsZ inhibitor drug candidate TXA709 as one of only 2 (out of 26) antibacterials targeting WHO priority pathogens that meet all of the WHO innovation criteria (absence of known cross resistance, new class, new target; new mode of action).
© 2024 TAXIS Pharmaceuticals, Inc.
Alan G.E. Wilson, PhD, Fellow ATS, FRSC
Alan G. E. Wilson, PhD, ATS, FRSC is currently Vice President of Drug Metabolism, Pharmacokinetics, and Toxicology and Pathology at Lexicon Pharmaceuticals, the Woodlands, Texas. He is internationally recognized in drug metabolism and pharmacokinetics and has over 30 years of experience working on product discovery and development for both small molecules and bio-therapeutics. His expertise is in the translation of early discovery data into the clinic with extensive experience in the conduct of pharmacokinetics in Phase 1-3 clinical studies and PK, PK/PD and population PK modeling. He has significant hands-on experience with the regulatory and GLP requirements for the conduct of ADME, PK and safety assessment studies to support regulatory submissions and clinical studies. He has contributed to, and led, successful IND, NDA and MAA submissions.
Prior to joining Lexicon, Dr. Wilson held senior management and leadership positions with major international pharmaceutical and life science companies (chemical, agricultural chemicals, pharmaceutical) including Monsanto, Searle, Pharmacia and Pfizer. He has been involved with the registration of a number of successful marketed products with experience in a number of therapeutic areas including cardiovascular, endocrinology (particularly diabetes), ophthalmology, arthritis, pain, NASH, and has extensive experience working with global regulatory agencies.
Dr. Wilson has Board of Director and Scientific Advisory experience with several companies. He is Board Certified in Toxicology and has over 130 publications, including editorship of several books. He has been an invited speaker and presenter at numerous domestic and international conferences.
Dr. Wilson received his Ph.D. in Drug Metabolism/PK from the University of Surrey, U.K. and his B.Sc. in Biochemistry from the University of Surrey, U.K.
Vincent H. Tam, Pharm.D., BCPS (Infectious Diseases)
Vincent H. Tam received a B.S. from the National University of Singapore, Singapore and his Pharm.D. from Albany College of Pharmacy in Albany, New York. He completed an infectious diseases pharmacy residency at Detroit Receiving Hospital in Detroit, Michigan and a clinical pharmacology / infectious diseases fellowship at Albany Medical College. He is currently a full Professor (tenured) at the University of Houston College of Pharmacy in Houston, Texas. He is board certified in pharmacotherapy with added qualifications in infectious diseases.
Dr. Tam is the (co-) author of over 140 peer-reviewed publications in antimicrobial pharmacokinetics / pharmacodynamics and infectious disease therapeutics. He is on the Editorial Boards of Antimicrobial Agents and Chemotherapy, and Journal of Global Antimicrobial Resistance. He has also served as a grant proposal reviewer for the National Institutes Health (NIH) and an ad hoc reviewer for more than 20 journals such as the Clinical Infectious Diseases, International Journal of Infectious Diseases, Journal of Antimicrobial Chemotherapy, Journal of Clinical Pharmacology, and Lancet Infectious Diseases.
Lynn Silver, Ph.D.
Dr. Silver’s expertise spans more than 30 years in the antibacterial discovery area. Her experience includes 21 years at Merck Research Laboratories where she conducted research and supervised groups involved in discovery efforts for new antibacterials in natural products and chemical collections, support of chemical synthetic projects on improved antibacterials, pre-clinical evaluation of antibacterial drug candidates and the study of antibacterial resistance. Dr. Silver has experience with many biotech start-ups, small and large pharmaceutical companies and venture capitalists in a variety of projects involving antibacterial discovery. Throughout her career, she authored significant research papers and reviews in the field of bacterial genetics, physiology, and biochemistry, as well as discovery and analysis of antibacterial agents. She is a member of ASM, the Editorial Board of Antimicrobial Agents and Chemotherapy, ASM Branch Lecturer, and is a member of several biotechnology company Scientific Advisory Boards.
Dr. Silver earned a doctorate at Tufts University in Molecular Biology and Microbiology and did her postdoctoral work on bacterial DNA replication at the Université de Genève, and on DNA replication biochemistry of bacteriophage T4 at the NIH.
Dean L. Shinabarger, Ph.D.
Dr. Shinabarger is CEO and owner of Micromyx, a microbiology services company located in Kalamazoo, Michigan. He received a B.S. in Biology in 1982 from Emporia State University and a Ph.D. in Microbiology from Louisiana State University in 1986. As a postdoctoral fellow in the laboratory of Dr. Leo Parks at North Carolina State University, Dr. Shinabarger studied sterol synthesis in yeast. In addition, he completed a second fellowship at the University of Illinois College of Medicine in Chicago under Dr. Chakrabarty, investigating Pseudomonas aeruginosa pathogenesis as related to cystic fibrosis patients’ lung infections. Dr. Shinabarger’s industrial career began in 1992 at Proctor & Gamble Pharmaceuticals in their anti-infective discovery program.
After 2 years, he moved to Upjohn Pharmaceuticals to join the discovery and development team working on the oxazolidinone class of antibacterial agents. Dr. Shinabarger played a major role in elucidating the mechanism of action/resistance to linezolid and represented Pharmacia during the FDA review and eventual approval of Zyvox in 2000. After Pfizer acquired Pharmacia in 2003, Dean exited the company and co-founded Micromyx, a microbiology services company that specializes in preclinical R&D for biotech, pharma, and animal health companies that are actively engaged in antibacterial and antifungal research.
Louis Donald Saravolatz, M.D., MACP
Dr. Saravolatz is recognized for his research in infectious disease, specifically in the areas of new drug therapies and rapid diagnostic microbiologic tests. He is currently Professor of Medicine and Chairman of the Department of Internal Medicine at St. John Hospital & Medical Center. The hospital is affiliated with Wayne State University School of Medicine, where he also serves as Director of Department of Medicine Molecular Biology Laboratory. Prior to his current role, he directed the infectious disease training program at Henry Ford Hospital for 14 years. Dr. Saravolatz has authored more than 400 articles, text book chapters, invited reviews and scientific presentations and serves as a member for over 16 professional societies, including The American College of Physicians, Infectious Disease Society of America and The American College of Epidemiology and the Royal Society of Medicine (London). He has received numerous honors and awards for his teaching ability and clinical expertise in infectious diseases and was made a Master of the American College of Physicians. In 2005, Dr. Saravolatz was awarded the academic achievement in medical management from the American College of Physicians Executive.
Dr. Saravolatz received his B.S from University of Michigan and earned his M.D from University of Michigan Medical School.
Daryl Patrick, DVM, Ph.D., Diplomat, ACVP
Specialist in Nonclinical Development for over 30 years, starting with Merck where Dr. Patrick ultimately served as Vice President/Head, Worldwide Safety Assessment, responsible for all nonclinical aspects of potential drug development candidates. Also served on Research and Development Management teams responsible for strategic R&D planning and oversight of drug development programs through approval. He then served as Vice President, Nonclinical Development at Vertex Pharmaceuticals, leading the establishment of disciplines in Toxicology and ADME to support early development efforts, then served on Management oversight committees and was promoted to Vice President, Exploratory Development responsible for all nonclinical development activities and Clinical Pharmacology. For the past several years since retiring from Vertex Pharmaceuticals, Dr. Patrick has engaged in private consulting for biotechnology and life sciences companies focused on novel therapeutic targets, serving on Scientific Advisory Boards providing guidance on nonclinical development activities and engagement with regulatory agencies around the world.
Dr. Patrick earned his D.V.M. in Veterinary Medicine from Michigan State University and his Ph.D. in Veterinary Pathology from Iowa State University.
Marshall Morningstar, Ph. D.
Marshall Morningstar is a pharmaceutical veteran with 20 years of experience managing small-molecule discovery teams in small biotechnology and large pharmaceutical companies. He is currently consulting for Sage Therapeutics (Neuroscience), Nimbus Therapeutics (Oncology), and Flatley Discovery Labs (Cystic Fibrosis). He was previously Director of Medicinal Chemistry at the Broad Institute directing a portfolio of neglected disease efforts. Before joining Broad, he was the Head of Chemistry for collaborative discovery efforts for GVK BIO, directing multiple programs in metabolic disorders, pain, and oncology research. Prior to GVK Bio, he spent over 11 years in the AstraZeneca infection group.
Marshall received a bachelor’s degree in chemistry from the University of California, Berkeley and a doctorate in synthetic organic chemistry from MIT.
David C. Hooper, M.D.
Dr. Hooper’s expertise is rooted in the molecular mechanisms of bacterial resistance to antimicrobial agents with a focus on quinolone resistance in Staphylococcus aureus and Escherichia coli. He previously served as President of the American Society for Microbiology, where he is currently the Meetings Board Chair. He is board certified in Internal Medicine and Infectious Disease, and Chief of the Infection Control Unit and Associate Chief and Fellowship Program Director of Division of Infectious Diseases at Massachusetts General Hospital.
Dr. Hooper received his B.A. in Microbiology from University of Texas at Austin. He earned his M.D. in Medicine from Washington University, and an Honorary M.A. from Harvard University.
David Kimball, Ph.D.
Dr. David Kimball joins TAXIS with more than 30 years of experience in the discovery and development of small molecule drug candidates. He currently serves as Associate Vice President for the Office of Research Commercialization (ORC) at Rutgers University. Dr. Kimball is also a Research Professor at the Ernest Mario School of Pharmacy.
Previously, Dr. Kimball was Chief Scientific Officer at Hydra Biosciences, a biopharmaceutical company focused on applying its understanding of Transient Receptor Potential (TRP) ion channels to the discovery of drugs for pain, inflammation and respiratory disease. He also served as Senior Vice President of Nonclinical Research at Pharmacopeia, Inc.
Dr. Kimball served as Vice President of Chemistry at Lexicon Pharmaceuticals, where he was responsible for building an organization of over 75 chemists, including medicinal, analytical, computational, process research and development, library synthesis and outsourcing chemistry. He spent the first 19 years of his career at Bristol-Myers Squibb Pharmaceutical Research Institute, most recently as Research Fellow in the Division of Medicinal Chemistry, Princeton, NJ.
Dr. Kimball earned his Ph.D. in Organic Chemistry/Chemical Biology from the State University of New York at Stony Brook.
Dr. Cimarusti has broad experience in pharmaceutical discovery, development and manufacturing. He served as Vice President of Process R&D at the Pharmaceutical Research Institute and as SVP of Pharmaceutical Development. Dr. Cimarusti held executive leadership
positions at Squibb Corporation and Bristol-Myers Squibb (BMS) in discovery and development, where he co-led the antibiotic effort and served as Director of Organic Chemistry for the Squibb Institute for Medical Research. He published more than 40 papers, and was inventor or co- inventor on more than 60 patents in the areas of cardiovascular, steroid, and b-lactam research, including both compound and process patents.
Dr. Cimarusti earned a Ph.D. in Organic Chemistry from Purdue University and completed Postdoctoral Research at Columbia University.
Ernest Mario, Ph.D.
Dr. Mario currently serves as Chairman of Capnia and Chimerix, and is a Venture Partner with Pappas Ventures, a life science venture capital firm. In addition to his current and past service on several corporate boards, Dr. Mario is active in numerous educational and healthcare organizations. He is Chairman of the American Foundation for Pharmaceutical Education, a Director of the Gladstone Foundation, and past Chairman of the Duke University Health System. Dr. Mario served in management at a number of drug companies before being named in 1989 Chief Executive of Glaxo. During his tenure, Glaxo brought five major new products to market and saw sales and profits increase by 15% annually. Later Dr. Mario led drug delivery technology company Alza until selling it to Johnson & Johnson in 2001. He subsequently served as Chairman and CEO of Reliant Pharmaceuticals. Dr. Mario holds honorary doctorates from the University of Rhode Island and Rutgers University, the latter of which in 2001 renamed its pharmacy school the Ernest Mario School of Pharmacy. In 2007 he was awarded the Remington Medal by the American Pharmacists’ Association, pharmacy’s highest honor.
Dr. Mario received his B.S. in pharmacy from Rutgers University, and M.S. and Ph.D. in physical sciences from the University of Rhode Island.
Dr. Parhi brings over 25 years of experience in the fields of organic chemistry, synthetic methodologies, natural product synthesis, medicinal chemistry, and drug discovery. Since the founding of TAXIS Pharmaceuticals, he has served as the Chief Medicinal Chemist and has led the company’s discovery research efforts since 2018. Currently, as the Chief Scientific Officer (CSO) at TAXIS, he oversees all drug discovery programs.
His extensive expertise encompasses synthetic medicinal chemistry and microbiology, coupled with a deep understanding of pharmacology and toxicology. Dr. Parhi’s adeptness in managing multi-million-dollar grants and his experience in collaborative, matrix-based environments position him as an exceptional leader to drive research and development at TAXIS.
An accomplished researcher, Dr. Parhi has authored and co-authored 40 peer-reviewed publications and is a co-inventor on over 30 patent applications. He has also received two prestigious federal grants from CARB-X and NIAID as principal investigator.
Dr. Parhi earned his Ph.D. from the City University of New York and completed his postdoctoral research at the University of Pennsylvania.
Gregory G. Mario, MBA, President and CEO
Mr. Mario joins TAXIS with more than 20 years of experience in the life sciences industry as a sales, marketing, business development, and licensing and acquisition professional. Prior to his role at TAXIS, he served as the Senior VP of Business Development with Talk America, a local-long distance telecommunications provider, and remains Partner at MFP, LP, a private equity investment entity focused on the life sciences sector. Mr. Mario co-founded the Brownstone Advisory Group, a real estate investment fund, and is a Director at Evogen, Inc., a development stage laboratory diagnostics company focused on central nervous system disease management.
Mr. Mario received a B.S. in Biochemistry from Trinity College. He earned an M.B.A. in Finance and Marketing at the Fuqua School of Business, Duke University as a Fuqua Scholar.
