Repurposing tebipenem pivoxil as alternative therapy for severe gastrointestinal infections caused by extensively-drug resistant (XDR) Shigella spp

Diarrhoea remains one of the leading causes of childhood mortality globally. Recent epidemiological studies conducted in low-middle income countries (LMICs) identified Shigella spp. as the first and second most predominant agent of dysentery and moderate diarrhoea, respectively. Antimicrobial therapy is often necessary for Shigella infections; however, we are reaching a crisis point with efficacious antimicrobials. The rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. Here, aiming to identify alternative antimicrobial chemicals with activity against multi-drug resistant (MDR) Shigella, we initiated a collaborative academia-industry drug discovery project, applying high throughput phenotypic screening across broad chemical diversity. We identified several suitable compounds with antibacterial activity against Shigella. These compounds included the oral carbapenem tebipenem, which was found to be highly potent against broadly susceptible Shigella and contemporary MDR variants. Additional in vitro screening demonstrated that tebipenem had activity against a wide range of other non-Shigella enteric bacteria. Cognisant of the risk for the development of resistance against monotherapy, we identified synergistic behaviour of two different drug combinations incorporating tebipenem. The orally bioavailable prodrug (tebipenem pivoxil) effectively cleared the gut of infecting organisms when administered in physiological doses to Shigella-infected mice and gnotobiotic piglets. Our data highlight the utility of broad compound screening for tackling the emerging antimicrobial resistance crisis and shows that tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs.