000151680 001__ 151680
000151680 005__ 20251017144629.0
000151680 0247_ $$2doi$$a10.1016/j.drup.2025.101213
000151680 0248_ $$2sideral$$a143339
000151680 037__ $$aART-2025-143339
000151680 041__ $$aeng
000151680 100__ $$0(orcid)0000-0002-8480-0325$$aRamón-García, Santiago
000151680 245__ $$aSanfetrinem, an oral ß-lactam antibiotic repurposed for the treatment of tuberculosis
000151680 260__ $$c2025
000151680 5060_ $$aAccess copy available to the general public$$fUnrestricted
000151680 5203_ $$aTuberculosis (TB) is historically the world’s deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB. Recently, a growing body of evidence indicates that later-generation carbapenems in the presence of β-lactamase inhibitors could play a role in TB treatment. However, most of these drugs can only be administered intravenously in the clinic. We performed a screening of β-lactams against intracellular Mycobacterium tuberculosis (Mtb) and identified sanfetrinem cilexetil as a promising oral β-lactam candidate. Preclinical in vitro and in vivo studies demonstrated that: (i) media composition impacts the activity of sanfetrinem against Mtb, being more potent in the presence of physiologically relevant cholesterol as the only carbon source, compared to the standard broth media; (ii) sanfetrinem shows broad spectrum activity against Mtb clinical isolates, including MDR/XDR strains; (iii) sanfetrinem is rapidly bactericidal in vitro against Mtb despite being poorly stable in the assay media; (iv) there are strong in vitro synergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in an in vivo model of infection. These data, together with robust pre-clinical and clinical studies of broad-spectrum carbapenem antibiotics carried out in the 1990s by GSK, identified sanfetrinem as having potential for treating TB and catalyzed a repurposing proof-of-concept Phase 2a clinical study (NCT05388448) in South Africa.
000151680 536__ $$9info:eu-repo/grantAgreement/EC/FP7/291799/EU/Neglected Diseases Tres Cantos Open Lab Campus/OPENLABCAMPUS$$9info:eu-repo/grantAgreement/EC/H2020/749058/EU/Beta-lactams for Tuberculosis Treatment/BLMs 4 TB$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 749058-BLMs 4 TB
000151680 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttps://creativecommons.org/licenses/by-nc/4.0/deed.es
000151680 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000151680 700__ $$aGonzález del Río, Rubén
000151680 700__ $$aArenaz-Callao, María Pilar
000151680 700__ $$aBoshoff, Helena I.
000151680 700__ $$aRullas, Joaquín
000151680 700__ $$aAnca, Sara
000151680 700__ $$aCacho Izquierdo, Mónica
000151680 700__ $$aPorras de Francisco, Esther
000151680 700__ $$aPérez Herrán, Esther
000151680 700__ $$aSantos-Villarejo, Angel
000151680 700__ $$aMendoza-Losana, Alfonso
000151680 700__ $$aFerrer-Bazaga, Santiago
000151680 700__ $$aThompson, Charles J.
000151680 700__ $$aBarros Aguirre, David
000151680 700__ $$aBates, Robert H.
000151680 773__ $$g80 (2025), 101213 [14 pp.]$$pDrug resist. updat.$$tDRUG RESISTANCE UPDATES$$x1368-7646
000151680 8564_ $$s2071833$$uhttps://zaguan.unizar.es/record/151680/files/texto_completo.pdf$$yVersión publicada
000151680 8564_ $$s2299181$$uhttps://zaguan.unizar.es/record/151680/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000151680 909CO $$ooai:zaguan.unizar.es:151680$$particulos$$pdriver
000151680 951__ $$a2025-10-17-14:25:32
000151680 980__ $$aARTICLE