Sanfetrinem, repurposing an oral beta-lactam with intracellular activity for the treatment of tuberculosis

Sanfetrinem, repurposing an oral beta-lactam with intracellular activity for the treatment of tuberculosis. Ramón-García, S. et al. The International Journal of Tuberculosis and Lung Disease. Volumen 23 Number 10 November 2019 Supplement 1. Page S591

New strategies in TB therapeutics are urgently needed to cure all forms of the disease; however, developing new antimicrobials is costly and lengthy. Drug repurposing represents a rapid approach to generate new TB treat- ments.
Beta-lactams have an exceptional record of clinical safe- ty. Used for decades to treat bacterial infections, they were regarded as ineffective against Mycobacterium tu- berculosis; however, the clinical efficacy of meropenem was recently shown [PMID:27433841]. While promis- ing, meropenem can only be administered intravenously, not practical against a disease for which oral drugs are needed.
Here, we described the discovery of the oral beta-lactam sanfetrinem cilexetil, a first-in-class tricyclic carbape- nem. Sanfetrinem was identified in a screen of ca. 2,000 beta-lactams as the most active against intracellular M. tuberculosis H37Rv (MICTHP1= 0.5 μg/mL), along with potent activity in 7H9 broth (MIC7H9= 1.5 μg/mL). Time-kill assays and confocal time-lapse microscopy confirmed its intracellular and rapid bactericidal activ- ity. To assess its potential for global implementation, sanfetrinem was tested against a panel of M. tubercu- losis strains, including drug-susceptible and MDR/XDR clinical isolates from different geographical origins: it was more active and with a narrow spectrum of activity (MIC90= 1-4 μg/mL) than the clinically active meropen- em (MIC90= 2-64 μg/mL), with these activities enhanced in the presence of clavulanate, although to a lesser ex- tent in the case of sanfetrinem. Finally, mouse studies confirmed the equipotency of sanfetrinem cilexetil (oral prodrug) compared to a combination of subcutaneous meropenem and oral amoxicillin/clavulanate. Sanfetrinem cilexetil was developed by GlaxoSmith- Kline in the 1990s and underwent phase 2 clinical tri- als for upper respiratory infections. Its development was stopped prior to Phase 3 primarily based on commercial considerations. Our results show that it could represent an ideal oral beta-lactam with the ability to progress rapidly into clinical implementation. A Phase 2a clinical study is planned for 2021.

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