Rampioni Giordano, Visca Paolo, Leoni Livia, Imperi Francesco
Department of Sciences, University Roma Tre, Rome, Italy.
Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.
Emerg Top Life Sci. 2017 Apr 21;1(1):13-22. doi: 10.1042/ETLS20160018.
Antibiotic resistance is a serious public health concern at the global level. Available antibiotics have saved millions of lives, but are progressively losing their efficacy against many bacterial pathogens, and very few new antibiotics are being developed by the pharmaceutical industry. Over the last few decades, progress in understanding the pathogenic process of bacterial infections has led researchers to focus on bacterial virulence factors as potential targets for 'antivirulence' drugs, i.e. compounds which inhibit the ability of bacteria to cause damage to the host, as opposed to inhibition of bacterial growth which is typical of antibiotics. Hundreds of virulence inhibitors have been examined to date in vitro and/or in animal models, but only a few were entered into clinical trials and none were approved, thus hindering the clinical validation of antivirulence therapy. To breathe new life into antivirulence research and speed-up its transfer to the clinic, antivirulence activities have also been sought in drugs already approved for different therapeutic purposes in humans. If effective, these drugs could be repositioned for antivirulence therapy and have an easier and faster transfer to the clinic. In this work we summarize the approaches which have led to the identification of repurposing candidates with antivirulence activities, and discuss the challenges and opportunities related to antivirulence therapy and drug repurposing. While this approach undoubtedly holds promise for boosting antivirulence drug research, some important issues remain to be addressed in order to make antivirulence drugs viable alternatives to traditional antibacterials.
抗生素耐药性是全球层面严重的公共卫生问题。现有的抗生素挽救了数百万人的生命，但对许多细菌病原体的疗效正逐渐丧失，而制药行业研发的新抗生素却寥寥无几。在过去几十年里，对细菌感染致病过程的认识取得了进展，这使得研究人员将重点放在细菌毒力因子上，将其作为 “抗毒力” 药物的潜在靶点，即抑制细菌对宿主造成损害能力的化合物，这与典型抗生素抑制细菌生长不同。迄今为止，已有数百种毒力抑制剂在体外和 / 或动物模型中进行了检测，但只有少数进入临床试验，且无一获批，从而阻碍了抗毒力疗法的临床验证。为了给抗毒力研究注入新活力并加速其向临床转化，人们还在已获批用于人类不同治疗目的的药物中寻找抗毒力活性。如果有效，这些药物可重新定位用于抗毒力治疗，并能更轻松、快速地进入临床。在这项工作中，我们总结了已确定具有抗毒力活性的药物重新定位候选药物的方法，并讨论了与抗毒力治疗和药物重新定位相关的挑战与机遇。虽然这种方法无疑有望推动抗毒力药物研究，但为了使抗毒力药物成为传统抗菌药物的可行替代品，仍有一些重要问题有待解决。
