Sanfetrinem, an oral beta-lactam antibiotic repurposed for the treatment of tuberculosis Articles uri icon

authors

  • RAMÓN GARCÍA, SANTIAGO
  • González del Río del Río, Rubén González del Río
  • Arenaz-Callao, María Pilar Arenaz-Callao
  • Boshoff, Helena I.
  • RULLAS, JOAQUIN
  • Anca, Sara
  • Cacho Izquierdo, Mónica Cacho Izquierdo
  • Porras de Francisco de Francisco, Esther Porras de Francisco
  • Pérez Herrán Herrán, Esther Pérez Herrán
  • SANTOS VILLAREJO, ÁNGEL
  • MENDOZA LOSANA, ALFONSO
  • Santiago Ferrer-Bazaga, Santiago Ferrer-Bazaga
  • J. THOMPSON, CHARLES
  • BARROS AGUIRRE, DAVID
  • BATES, ROBERT H.

publication date

  • May 2025

issue

  • 101213

volume

  • 80

International Standard Serial Number (ISSN)

  • 1368-7646

Electronic International Standard Serial Number (EISSN)

  • 1532-2084

abstract

  • 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.

subjects

  • Biology and Biomedicine
  • Pharmacy

keywords

  • sanfetrinem; repurposing; tuberculosis; β-lactams; intracellular.