The worldwide resurgence of antibiotic resistant Gram-positive bacteria, especially Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium and Streptococcus pneumoniae, has stimulated discovery of novel agents that can selectively attack new bacterial targets. Through synthesis and study of compounds containing inhibitors of two validated drug targets, we have created a novel family of potent antibacterials that are rapidly bactericidal to all classes of Gram-positive bacteria. The results of phase II have provided development candidates of this new class of """"""""hybrid"""""""" antibiotic compounds active against drug-resistant Gram-positive bacteria. The class consists of a DNA polymerase IIIC inhibitor (anilinouracil, AU) covalently attached to a topoisomerase/gyrase inhibitor (fluoroquinolone, FQ). These new """"""""AU-FQ"""""""" hybrid compounds are tenfold more potent than conventional pol IIIC inhibitors, and have broader activity against clinical isolates of Gram-positive bacteria than the fluoroquinolones, both in vitro and in vivo. The development candidates are racemic 3-{4-[1-(1-cyclopropyl-3-carboxy-4-oxo-6,8-difluoro-7-quinolyl)-4-(2-methylpiperazinyl)]butyl}-6-(3-ethyl-4-methylanilino)uracil, and its S and R enantiomers. The rational selection of one compound as the candidate for development (CD) and its preclinical development for treatment of antibiotic-resistant staphylococcal and enterococcal infections are the subjects of the competing continuation application of this phase II SBIR grant. The goals of this project are, broadly, to: 1. optimize the process for synthesis of the development candidates, both to prepare material for preclinical studies and to provide methods for outsourcing cGMP production, and develop analytical methods to support drug product purity assays and pharmacokinetic analyses; 2. designate the CD based on IV pharmacokinetics in rats, toxicity evaluation in rats after continuous IV infusion, and efficacy evaluation in rat endocarditis models after continuous IV infusion; 3. carry out IND-enabling preclinical studies, including standard FDA required toxicology, pathology and toxicokinetic assays under GLP standards, and; 4. submit a Investigational New Drug (IND) application to the Food and Drug Administration (FDA) to enter human clinical trials. The CD will be targeted for parenteral administration to hospitalized patients with antibiotic-resistant Gram-positive infections. GLSynthesis and Microbiotix will continue a collaborative partnership in drug discovery and development by successful completion of this project. ? ?
| Butler, Michelle M; Shinabarger, Dean L; Citron, Diane M et al. (2012) MBX-500, a hybrid antibiotic with in vitro and in vivo efficacy against toxigenic Clostridium difficile. Antimicrob Agents Chemother 56:4786-92 |
