袁宗辉兽用抗菌药研发趋势

袁宗辉兽用抗菌药研发趋势 兽用抗菌药研发趋势 袁 宗 辉 国家兽药残留基准实验室(HZAU) 国家兽药安全(环境风险)评价实验室 农业部兽药残留 检测重点实验室 华中农业大学兽药研究所 Tel: 027-8728 7186，Fax: 027-8767 2232 E-mail: yuan5802@mail.hzau.edu.cn 内 容 提 要 问题提出 抗菌药替代品研发动态 抗菌药研发方向 1. 问 题 提 出 抗菌药是防治动物疾病最重要的武器 控制动物的细菌性疾病 控制动物的寄生虫病 控制动物的普通病(机能障碍) 控制动物 病毒病的继发感染 控制人畜共患病，如磺胺药、金霉素 抗菌药是改善动物生产性能的有效物质 促进生长 改善饲料利用率 提高畜禽的繁殖性能 降低胴体废弃率 改善皮毛质量 减少 动物污染物排放 节省了消费者的食物开支 抗菌药不合理使用的问题 毒副作用与药源性疾病 耐药性 残留 环境污染 解决问题的办法 (the 3 R’s Approach) Refinement (精准使用) 诊断确实 结构改造 药代动力学和PK-PD研究 Reduction (减 少使用) 预防感染 改善诊断 PK-PD研究 建立治疗新概念 Replacement (寻找替代品) 2. 抗菌药替代品研发动态 正在研发中的抗菌药替代品 抗菌疫苗 噬菌体 酶制剂 微生态制剂 中草药及其提取物 群体感应及生物被膜抑制剂 抗菌肽 抗 菌 疫 苗 The success: vaccination against furunculosis (Aeromonas salmonicida) in salmons reduced AB use by 98% (WHO, 2006). The following: mandatory vaccination of breeders against S. enteritidis in areas with > 10% prevalence Tailor-made approaches targeting multiple antigens Photo-targeting (nano-technology, Fecontaining disinfectants) Bacteriophages (bacteriovirusses) Morphologic classification (shape of the tail) no total 5 x 1031 Myoviridae Siphoviridae Podoviridae E.coli T4 1st described in 1896 (cholera) Marketed in 1920s: Colo-lysate, Staphylo-lysate; Bacté-pyo-phage; Replaced by antibiotics in 1940s 1st tested in animal farming 1987 (Smith & Huggins, 1983) Examples of current products: LMP102 and Listex P100 (Listeria) – meat treatment BacWash (Salmonella) – lifestock treatment High specificity an unresolved problem: cocktails Mechanism-based selection 酶 制 剂 消化酶类 淀粉酶类:α-淀粉酶，β-淀粉酶，糖化酶，异淀粉酶。 蛋白酶类:动物蛋 白酶，植物蛋白酶，微生物蛋白酶。 脂肪酶 非消化酶类 纤维素酶系 半纤维素酶 β-葡聚 糖酶 果胶酶 植酸酶 微生态制剂 Competetive exlusion:pro- and prebiotics (1831/2003/EC) 益生素 (Probiotics): 维持肠道内微生物平衡的微生物或物 质，包含抗生素。 低聚糖 (Oligosacharides)，又称 寡糖或寡聚糖，通常是指糖单 元通过糖苷键连接形成的直链或支链的聚合度为2,10的单糖 基聚 合物。又称为化学益生素 (Prebiotics)。 协生素 (Synbiotics):益生素和协生素的 统称。 菌体本身及其所分泌的化学物质的危害远远大于单一的抗生素～ 益生菌能接受和传 播耐药性 中草药与植物提取物 中草药 活性成分不清楚 代谢不明 有效性和安全性无法控制 植物提取物 生物活性物质 调节肠道菌丛 调节免疫 刺激动物生长 健胃 Quorum sensing: An emerging therapeutic target Autoinducers Gram + agr (RNAIII)- auto-inducing peptides (AIP) Proto type: TP-1 Hamamelitannin = inhibitor of MRSA & MRSE Gram – Acyl-homoserine lactones (AHL) Proto type: SAM-analoga QS-inhibitors ADHESION & Expression of virulence factors inhibited Planktonic cells LuxR Interspecies communication: LuxS/AI-2 signaling Inter-kingdom signalling: AI-3/epinephrine/norepinephrine i.e. Salmonella, E. coli, Haemophilus influenza, Shigella and APP A fruitful aliance Many PSMs, such as phenoles, quinines, flavonoids, terpenoids seem to act as quorum sensing inhibitors or modulators as well, and hence exert anti-virulent and antipathogenic activities, which might not be related to (the commonly assessed) growth and inhibition of microorganisms. Bacterial Viral & Fungal Infections 细菌的群体感应及其抑制原理 Quorum sensing & biofilms 5. Dispersion Planktonic cells 2. ECM PRODUCTION 1. ADHESION & Experssion of virulence factors 3. BIOFILM ARCHITURE 4. BIOFILM MATURATION Phytobiotics: a re-discovered source of new molecules (non-compliance with common HT-testing) 抗 菌 肽 养殖动物使用的肽类抗生素不下十种 目前关注的抗菌肽(AMPs or defensins): antimicrobial (cationic) peptides originating from bacteria or eukaryotic cells acting as quorum sensing inhibitors Bacterial cell wall hydrolases (endolysinen): lysis of gram + Lantibiotica (lanthionine-containing):lysis (lipid II) of gram – 抗菌肽也能诱导耐药性～ 3. 兽用抗菌药研发方向 兽用抗菌药新产品研发 新化合物实体的发明与发现 原有化合物的结构和性质改造 现有药物剂型的发明与改造 现有药物的药代动力学深入研究 PK-PD研究 新型复方制剂研发 建立新型防治理论，研发抗 菌药合理使用的新 技术 A brief history of antibiotic development 原有化合物的结构和性质改造 β-内酰胺类通过结构改造出现一系列耐酸、耐酶、广 谱、高效的新药，四环素类、酰 胺醇类、大环内酯类、 磺胺类、氟喹诺酮类无不如此 近年结构改造的成功例子 乙酰异戊酰 泰乐菌素 (超级泰乐菌素) 土拉霉素 (Tulathromycin) 近年改变化合物性质的成功例子 头 孢噻呋游离酸 Transports and Pharmacokinetics Major Routes of Drug Elimination High Solubility High Permeability Low Solubility Class 1 Metabolism Class 2 Metabolism Low Permeability Class 3 Renal & Biliary Elimination of Unchanged Drug Class 4 Renal & Biliary Elimination of Unchanged Drug Benet. LZ, (2005), AAPS Workshop on Drug Transporters in ADME: From the Bench to the Bedside March 8, 2005 Oral Dosing Transporter Effects High Solubility High Permeability Low Solubility Class 1 Transporter effects minimal Class 2 Efflux transporter effects predominate Low Permeability Class 3 Absorptive transporter effects predominate Class 4 Absorptive and efflux transporter effects could be important Benet. LZ, (2005), AAPS Workshop on Drug Transporters in ADME: From the Bench to the Bedside March 8, 2005 Mutant Selection Window Antibiotic concentration Risk area : Resistant bacteria selection MPC = MIC of resistant bacteria MIC T>MPC TMSW Time PK/PD Indices MIC : Minimum Inhibitory Concentration MPC : Mutant Prevention Concentration MSW : Mutant Selection Window Time above the MPC: T>MIC Time above the MPC: T>MPC Time within the MSW: TMSW Time-dependent antibiotics Bacteriostatic Bactericidal Main parameter: time above MIC (T> MIC) Time above MIC (T> MIC) Bactericidal Cephalosporines Penicillines Tetracyclines 60 % 50 % 50 % () Bacteriostatic 40 % 40 % 30 % Clinical efficacy and resistance development of concentration-dependent antibiotics AUIC > 250 AUIC > 125 AUIC > 60 AUIC = 30 – 60 AUIC < 20 Normally not attainable Gram- bacteria (enterobacteriaceae) Gram+ bacteria resistance development Too low antibacterial activity Low resistance development No antibacterial activity 科学地联合使用抗菌药 联合用药的指征 混合感染 病因不明的严重感染 一种药长期使用易产生耐药性 减少用 量、降低毒副作用 推荐的联合用药 青霉素 + 链霉素 磺胺药 + TMP 阿莫西林 + 克拉维酸 应避免的联合用药 速效杀菌剂 + 速(慢)效制菌剂 作用于邻近靶位的细菌蛋白合 成抑制剂 (酰胺醇类、四环素类、 大环内酯类、林可胺类)。 抗菌药协同杀菌机制 Therapeutic concepts AB AB AB AB + NSAIDs + NSAIDs + NSAIDs + Symptomatic + Symptomatic Tissue Repair + Improvement of therapeutic efficiency， Reduction of economic losses The time course of the bacterial disease Health Start of the infectious disease Disease No symptoms Symptoms PROPHYLAXIS METAPHYLAXIS (few) (few ) PREVENTIVE EARLY conventional CURATIVE TREATMENT Resistant mutant selection The same dosage regimen Metaphylaxis susceptible population resistant mutants population Conventional treatment susceptible population resistant mutants population Resistant mutants prevention Resistant mutants selection Preventive medicine Primary prevention avoids the development of a disease. Most population-based health promotion activities are primary preventive measures Secondary prevention activities are aimed at early disease detection, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms. Tertiary prevention reduces the negative impact of an already established disease by restoring function and reducing disease-related complications. The Most Important Administration Routes of Veterinary Medicines Medicated feed 67% Parenteral Others 7% 2% Drinking water medication 24% Mass medication or flock treatment mainly applied for pigs and poultry General sale of medication : > 80 % for pigs and poultry Mainly : antibiotics and antiparasitics Veterinary health care: one world – one health! 谢 谢～