title: Preclinical development of Ramizol, an antibiotic belonging to a new class, for the treatment of Clostridium difficile colitis.
abstract: Antibiotic-resistant bacteria is a major threat to human health and is predicted to become the leading cause of death from disease by 2050. Despite the recent resurgence of research and development in the area, few antibiotics have reached the market, with most of the recently approved antibiotics corresponding to new uses for old antibiotics, or structurally similar derivatives thereof. We have recently reported an in silico approach that led to the design of an entirely new class of antibiotics for the bacteria-specific mechanosensitive ion channel of large conductance: MscL. Here, we present the preclinical development of one such antibiotic, Ramizol, a first generation antibiotic belonging to that class. We present the lack of interaction between Ramizol and other mammalian channels adding credibility to its MscL selectivity. We determine the pharmacokinetic profile in a rat model and show <0.1% of Ramizol is absorbed systemically. We show this non-systemic nature of the antibiotic translates to over 70% survival of hamsters in a Clostridium difficile colitis model. Lastly, initial in vitro data indicate that resistance to Ramizol occurs at a low frequency. In conclusion, we establish the potential of Ramizol as an effective new treatment for C. difficile associated disease.
authors.affiliation: School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia.
authors.forename: Shasha
authors.initials: S
authors.lastname: Rao
authors.affiliation: School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia.
authors.forename: Clive A
authors.initials: CA
authors.lastname: Prestidge
authors.affiliation: Eurofins Panlabs Ltd, Taipei, Taiwan.
authors.forename: Lynn
authors.initials: L
authors.lastname: Miesel
authors.affiliation: Micromyx LLC., Kalamazoo, MI, USA.
authors.forename: Deb
authors.initials: D
authors.lastname: Sweeney
authors.affiliation: Micromyx LLC., Kalamazoo, MI, USA.
authors.forename: Dean L
authors.initials: DL
authors.lastname: Shinabarger
authors.affiliation: School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA, Australia.|Antibiotic Development, Boulos & Cooper Pharmaceuticals Pty Ltd, Port Adelaide, SA, Australia.
authors.forename: Ramiz A
authors.initials: RA
authors.lastname: Boulos
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016360:Clostridioides difficile / Q000187:drug effects; D003015:Clostridium Infections / Q000188:drug therapy*; D003092:Colitis / Q000188:drug therapy* / Q000382:microbiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D024901:Drug Resistance, Multiple, Bacterial; D008297:Male; D008647:Mesocricetus; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D001565:Benzoates; D013267:Stilbenes; C000601530:Ramizol