Sanfetrinem, an oral β-lactam antibiotic repurposed for the treatment of tuberculosis.

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 () and identified sanfetrinem cilexetil as a promising oral β-lactam candidate. Preclinical and studies demonstrated that: (i) media composition impacts the activity of sanfetrinem against , 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 clinical isolates, including MDR/XDR strains; (iii) sanfetrinem is rapidly bactericidal against despite being poorly stable in the assay media; (iv) there are strong synergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in an 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) currently underway in South Africa.