Fernández Álvaro Elena, Voong Vinh Phat, de Cozar Cristina, Willé David R, Urones Beatriz, Cortés Alvaro, Price Alan, Tran Do Hoang Nhu, Ha Thanh Tuyen, McCloskey Molly, Shaheen Shareef, Dayao Denise, Martinot Amanda, de Mercado Jaime, Castañeda Pablo, García-Perez Adolfo, Singa Benson, Pavlinac Patricia, Walson Judd, Martínez-Martínez Maria Santos, Arnold Samuel L M, Tzipori Saul, Ballell Pages Lluis, Baker Stephen
GSK Global Health, Tres Cantos, Madrid, Spain.
The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam.
Elife. 2022 Mar 15;11:e69798. doi: 10.7554/eLife.69798.
Diarrhoea remains one of the leading causes of childhood mortality globally. Recent epidemiological studies conducted in low-middle income countries (LMICs) identified spp. as the first and second most predominant agent of dysentery and moderate diarrhoea, respectively. Antimicrobial therapy is often necessary for infections; however, we are reaching a crisis point with efficacious antimicrobials. The rapid emergence of resistance against existing antimicrobials in spp. poses a serious global health problem.
Aiming to identify alternative antimicrobial chemicals with activity against antimicrobial resistant , we initiated a collaborative academia-industry drug discovery project, applying high-throughput phenotypic screening across broad chemical diversity and followed a lead compound through in vitro and in vivo characterisation.
We identified several known antimicrobial compound classes with antibacterial activity against . These compounds included the oral carbapenem Tebipenem, which was found to be highly potent against broadly susceptible and contemporary MDR variants for which we perform detailed pre-clinical testing. Additional in vitro screening demonstrated that Tebipenem had activity against a wide range of other non- enteric bacteria. Cognisant of the risk for the development of resistance against monotherapy, we identified synergistic behaviour of two different drug combinations incorporating Tebipenem. We found the orally bioavailable prodrug (Tebipenem pivoxil) had ideal pharmacokinetic properties for treating enteric pathogens and was effective in clearing the gut of infecting organisms when administered to -infected mice and gnotobiotic piglets.
Our data highlight the emerging antimicrobial resistance crisis and shows that Tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) should be accelerated into human trials and could be repurposed as an effective treatment for severe diarrhoea caused by MDR and other enteric pathogens in LMICs.
Tres Cantos Open Lab Foundation (projects TC239 and TC246), the Bill and Melinda Gates Foundation (grant OPP1172483) and Wellcome (215515/Z/19/Z).
腹泻仍是全球儿童死亡的主要原因之一。最近在低收入和中等收入国家（LMICs）进行的流行病学研究分别确定了 菌属为痢疾和中度腹泻的第一和第二大主要病原体。对于 感染，抗菌治疗通常是必要的；然而，我们正面临有效抗菌药物的危机点。 菌属中对现有抗菌药物耐药性的迅速出现构成了严重的全球健康问题。
为了确定对耐药 具有活性的替代抗菌化学物质，我们启动了一个产学研合作的药物发现项目，在广泛的化学多样性中应用高通量表型筛选，并通过体外和体内表征追踪一种先导化合物。
我们确定了几种对 具有抗菌活性的已知抗菌化合物类别。这些化合物包括口服碳青霉烯类药物替比培南，发现它对广泛敏感的 以及当代多重耐药变体具有高效力，我们对这些变体进行了详细的临床前测试。额外的体外筛选表明，替比培南对多种其他非 肠道细菌具有活性。认识到单药治疗产生耐药性的风险，我们确定了两种包含替比培南的不同药物组合的协同作用。我们发现口服生物可利用的前药（替比培南匹伐酯）具有治疗肠道病原体的理想药代动力学特性，并且在给感染 的小鼠和无菌仔猪给药时，能有效清除肠道中的感染生物体。
我们的数据突出了新出现的抗菌药物耐药性危机，并表明替比培南匹伐酯（在日本已获儿科呼吸道感染许可）应加速进入人体试验，并且可以重新用作治疗 LMICs 中由多重耐药 和其他肠道病原体引起的严重腹泻的有效药物。
特雷斯坎托斯开放实验室基金会（项目 TC239 和 TC246）、比尔及梅琳达·盖茨基金会（赠款 OPP1172483）和惠康基金会（215515/Z/19/Z）
