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1.
Nature ; 625(7995): 566-571, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38172634

RESUMEN

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.


Asunto(s)
Antibacterianos , Lipopolisacáridos , Proteínas de Transporte de Membrana , Animales , Humanos , Ratones , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/metabolismo , Antibacterianos/clasificación , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Lipopolisacáridos/metabolismo , Pruebas de Sensibilidad Microbiana , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico/efectos de los fármacos , Modelos Animales de Enfermedad , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Desarrollo de Medicamentos
3.
Toxicol Rep ; 8: 1960-1969, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34926173

RESUMEN

Guidelines regulating the development of advanced therapy medicinal products (ATMPs) request nonclinical data for toxicity, biodistribution and tumorigenicity before mesenchymal stromal cell (MSC) products can be administered in large clinical trials. We assessed the biodistribution/persistence, safety and tumorigenicity of MC0518, a human allogeneic MSC product from pooled bone marrow mononuclear cells of eight healthy, adult, unrelated donors, which is currently investigated for the treatment of steroid-refractory acute Graft-versus-Host Disease (aGvHD) after hematopoietic stem cell transplantation. In our GLP studies, immuno-deficient mice were administered repeat doses of MC0518 (once weekly for 6 weeks, i.v.) at doses exceeding the proposed human clinical dose 20-60-fold. No signs of toxicity were observed in the combined biodistribution/toxicity study. Human MSCs in mouse tissues were detected by quantitative PCR (qPCR) and in situ hybridization (ISH). MC0518 showed initial trapping in the lung, occasional distribution into other organs and low tissue persistence beyond 24 h after application. No MSC-induced tumors of human origin were identified after a follow-up of six months. Additionally, we found that the combination of different detection methods (qPCR and ISH) is crucial for a reliable interpretation of biodistribution results. Our data suggest that MC0518 is safe for use in human.

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