151680 20251017144629.0 doi 10.1016/j.drup.2025.101213 sideral 143339 ART-2025-143339 eng Ramón-García, Santiago (orcid)0000-0002-8480-0325 Sanfetrinem, an oral ß-lactam antibiotic repurposed for the treatment of tuberculosis 2025 Access copy available to the general public Unrestricted Tuberculosis (TB) is historically the world’s deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB. Recently, a growing body of evidence indicates that later-generation carbapenems in the presence of β-lactamase inhibitors could play a role in TB treatment. However, most of these drugs can only be administered intravenously in the clinic. We performed a screening of β-lactams against intracellular Mycobacterium tuberculosis (Mtb) and identified sanfetrinem cilexetil as a promising oral β-lactam candidate. Preclinical in vitro and in vivo studies demonstrated that: (i) media composition impacts the activity of sanfetrinem against Mtb, being more potent in the presence of physiologically relevant cholesterol as the only carbon source, compared to the standard broth media; (ii) sanfetrinem shows broad spectrum activity against Mtb clinical isolates, including MDR/XDR strains; (iii) sanfetrinem is rapidly bactericidal in vitro against Mtb despite being poorly stable in the assay media; (iv) there are strong in vitro synergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in an in vivo model of infection. These data, together with robust pre-clinical and clinical studies of broad-spectrum carbapenem antibiotics carried out in the 1990s by GSK, identified sanfetrinem as having potential for treating TB and catalyzed a repurposing proof-of-concept Phase 2a clinical study (NCT05388448) in South Africa. info:eu-repo/grantAgreement/EC/FP7/291799/EU/Neglected Diseases Tres Cantos Open Lab Campus/OPENLABCAMPUS info:eu-repo/grantAgreement/EC/H2020/749058/EU/Beta-lactams for Tuberculosis Treatment/BLMs 4 TB This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 749058-BLMs 4 TB info:eu-repo/semantics/openAccess by-nc https://creativecommons.org/licenses/by-nc/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion González del Río, Rubén Arenaz-Callao, María Pilar Boshoff, Helena I. Rullas, Joaquín Anca, Sara Cacho Izquierdo, Mónica Porras de Francisco, Esther Pérez Herrán, Esther Santos-Villarejo, Angel Mendoza-Losana, Alfonso Ferrer-Bazaga, Santiago Thompson, Charles J. Barros Aguirre, David Bates, Robert H. 80 (2025), 101213 [14 pp.] Drug resist. updat. DRUG RESISTANCE UPDATES 1368-7646 2071833 http://zaguan.unizar.es/record/151680/files/texto_completo.pdf Versión publicada 2299181 http://zaguan.unizar.es/record/151680/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:151680 articulos driver 2025-10-17-14:25:32 ARTICLE