Antibiotic discovery from environmental microorganisms of Brazil

摘要 我们目前正在经历一场抗菌素耐药性的危机，世界卫生组织发现 需要与耐药的革兰氏阴性病原体作“危急”斗争。最后一类起作用的化合物 革兰氏阴性细菌是在50多年前引入的。 预防抗菌素耐药性的最有效策略是引入新的化合物， 对AMR病原体起作用，并具有较低的抗药性发展几率。我们最近确定了一部小说 抗菌剂teixobactin，对革兰氏阳性细菌没有检测到耐药性(Ling等人，自然 2015年)。Teixobactin目前正在开发用于治疗重要的革兰氏阳性AMR感染的药物 如MRSA菌血症。我们最近发现了另一种天然产品抗生素达罗巴汀，具有 对革兰氏阴性AMR病原体的抗药性异常低。 虽然这些都是令人鼓舞的进步，但在重新发现同样的进步上花费了相当大的努力 产生物种和化合物。我们认为，利用我们的资源开采巴西丰富的土壤 方法将提供获得新型抗生素的途径，以对抗AMR危机。巴西热带雨林拥有 植物和动物的多样性最高，我们预计微生物也是如此。的确， 微生物直接或松散地与真核生物结合，降解其产物。这个项目的目标是 是评估巴西土壤的微生物多样性，筛选革兰氏阴性化合物的分离株 活性，并分离和验证新的抗菌剂。如果我们能够从土壤中找到新的抗菌剂 在新英格兰，有理由期待一旦我们进入一个环境，发现的速度将会加快 拥有地球上最丰富的多样性。 该项目汇集了东北大学的金·刘易斯博士，他是耐药性方面的专家， 圣保罗大学的药物发现专家莫妮卡·普波博士和天然产物化学专家莫妮卡·普波博士。这些 科学家们共同撰写了这份提案，并将在执行过程中密切合作。

Abstract We are currently experience a crisis of antimicrobial resistance, and the World Health Organization identified the need to combat drug resistant Gram negative pathogens as “critical”. The last class of compounds acting against Gram negative bacteria was introduced over 50 years ago. The most effective strategy to prevent antimicrobial resistance is by introducing novel compounds that act against AMR pathogens and have low probability of resistance development. We recently identified a novel antimicrobial, teixobactin, that shows no detectable resistance against Gram positive bacteria (Ling et al., Nature 2015). Teixobactin is currently in IND-enabling development against important Gram positive AMR infections such as MRSA bacteremia. We more recently discovered another natural product antibiotic, darobactin, with unusually low resistance development that acts against Gram negative AMR pathogens. While these are encouraging advances, a considerable effort is spent on rediscovery of the same producing species and compounds. We reason that mining the rich diversity of Brazilian soils with our approaches will provide access to novel antibiotic to combat the AMR crisis. The Brazilian rain forest has the highest diversity of plants and animals, and we expect the same to be true for microorganisms. Indeed, microorganism directly or loosely associate with eukaryotes, and degrade their products. The goal of this project is to evaluate soils from Brazil for their microbial diversity, to screen isolates for compounds with Gram negative activity, and to isolate and validate novel antimicrobials. If we are able to find novel antimicrobials from soils of New England, it is reasonable to expect that the pace of discovery will increase once we access an environment with the richest diversity on the planet. This project brings together Dr. Kim Lewis, Northeastern University, an expert in drug resistance and drug discovery, and Dr. Monica Pupo, University Sao Paulo, an expert in natural products chemistry. These scientists collaborated on writing the proposal and will work closely together on its execution.