Novel antimicrobials for swine health

随着众多感染性细菌对抗生素耐药性的提高，抗菌肽被认为是替代传统抗生素的最佳候选药物之一。AMP是由大多数生物体的免疫系统产生和利用的。大多数自然产生的AMP对几种类型的感染性细菌都有活性，但在治疗剂量下，它们中的许多对哺乳动物是有毒的。利用机器学习(ML)方法，结合我们目前对天然AMP的了解，我们可以发现对哺乳动物毒性小得多、抗病原体效果更好的新型AMP。在这个项目中，我们将使用ML来开发新型AMP，专门针对养猪场的肠道沙门氏菌感染。来自先前已知和研究的AMP的数据将被用作ML计算的输入。在这个项目预计的两年内，我们希望提供更好的抗菌剂来治疗猪的肠道沙门氏菌感染。使用ML方法发现的AMP将在体外测试其抗菌活性和细胞毒性。这一阶段的最佳候选AMP的二级结构将通过核磁共振光谱确定，并用于原子分子动力学模拟，以获得抗微生物活性的详细图像。我们将通过一些体外测试来检验我们的最佳候选AMP(目前为HHC-36)的有效性和对蛋白质降解的抵抗力。当口服给受感染的动物时，我们要求多肽抵抗消化酶和胃的高度酸性环境的降解。因此，我们将研究多肽通过模拟猪的肠道轨迹时的存活率。如果需要，还将考虑使用胶囊将多肽保存在猪的消化系统中，并建议用于未来的动物试验等给药方法。

With development of antibacterial resistance among numerous strains of infectious bacteria, antimicrobial peptides (AMPs) are considered to be among the best candidates to replace traditional antibiotics. AMPs are produced and employed by immune system of most organisms.Most of the naturally occurring AMPs are active against several types of infectious bacteria, but many of them are toxic to mammalians at therapeutic dosages. Use of machine learning (ML) methods, together with our current knowledge of natural AMPs, we can discover novel AMPs, with much less toxicity to mammalians and increased effectiveness against pathogens.In this project, we will use ML to develop novel AMPs, specifically for targeting the intestinal salmonella infections in pig farms. Data from previously known and studied AMPs will be used as input to the ML calculations. Within a projected two-year period for this project, we expect to deliver better antimicrobials for treating intestinal salmonella infections in pigs. AMPs discovered using ML methods will be tested in vitro for their antimicrobial activity and cytotoxicity. The secondary structure of the best candidate AMPs from this stage will be determined using nuclear magnetic resonance spectroscopy and used in atomistic molecular dynamics simulations to obtain a detailed picture of antimicrobial activity.We will examine our best candidate AMP (currently, HHC-36) for its effectiveness and resistance to proteolytic degradation through a number of in vitro tests.When administered orally to the infected animal, we require that the peptide resists to degradation by the digestive enzymes and the highly acidic environment of the stomach. We will therefore study the survival rate of the peptide as it passes through simulated intestinal track of the swine. If needed, delivery methods such as use of capsules for preserving the peptide in the pig's digestive system will also be considered and proposed for future animal trials.