Novel antimicrobials for swine health

随着感染性细菌耐药性的不断增强，抗菌肽被认为是替代传统抗生素的最佳候选药物之一。抗菌肽是由机体免疫系统产生和利用的，大多数天然抗菌肽对多种感染性细菌具有抗菌活性，但在治疗剂量下，许多抗菌肽对人体有毒性。利用机器学习（ML）方法，结合我们现有的天然抗菌肽知识，我们可以发现新的抗菌肽，对猪的毒性更小，对病原体的有效性更高。在这个项目中，我们将使用ML开发新的抗菌肽，专门针对猪场的肠道沙门氏菌感染。来自先前已知和研究的AMP的数据将用作ML计算的输入。在该项目预计的两年时间内，我们预计将提供更好的抗菌剂来治疗猪肠道沙门氏菌感染。使用ML方法发现的抗菌肽将在体外测试其抗菌活性和细胞毒性。来自该阶段的最佳候选AMP的二级结构将使用核磁共振光谱法确定，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。（目前，HHC-36）通过许多体外试验证明其有效性和对蛋白水解降解的抗性。我们要求肽抵抗消化酶和胃的高酸性环境的降解。因此，我们将研究肽通过猪的模拟肠道时的存活率。如果需要，还将考虑使用胶囊等递送方法将肽保存在猪的消化系统中，并提议用于未来的动物试验。

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.