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