RESUMO
Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options1. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years1. Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB2FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB2FGC as a tractable target for antimicrobial drug development.
Assuntos
Antibacterianos , Lipopolissacarídeos , Proteínas de Membrana Transportadoras , Animais , Humanos , Camundongos , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/metabolismo , Antibacterianos/classificação , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Lipopolissacarídeos/metabolismo , Testes de Sensibilidade Microbiana , Proteínas de Membrana Transportadoras/metabolismo , Transporte Biológico/efeitos dos fármacos , Modelos Animais de Doenças , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Desenvolvimento de MedicamentosRESUMO
This study describes a novel Miniaturized INtrinsic DISsolution Screening (MINDISS) assay for measuring disk intrinsic dissolution rates (DIDR). In MINDISS, compacted mini disks of drugs (2-5mg/disk) are prepared in custom made holders with a surface area of 3mm(2). Disks are immersed, pellet side down, into 0.35ml of appropriate dissolution media per well in 96-well microtiter plates, media are stirred and disk-holders are transferred to new wells after defined periods of time. After filtration, drug concentration in dissolution media is quantified by Ultra Performance Liquid Chromatography (UPLC) and solid state property of the disk is characterized by Raman spectroscopy. MINDISS was identified as an easy-to-use tool for rapid, parallel determination of DIDR of compounds that requires only small amounts of compound and of dissolution medium. Results obtained with marketed drugs in MINDISS correlate well with large scale DIDR methods and indicate that MINDISS can be used for (1) rank-ordering of compounds by intrinsic dissolution in late phase discovery and early development, (2) comparison of polymorphic forms and salts, (3) screening and selection of appropriate dissolution media, and (4) characterization of the intestinal release behavior of compounds along the gastro intestinal tract by changing biorelevant media during experiments.