Han Jianying, Bruhn David F, Childs Cynthia T, Moreno Yovany, Salim Angela A, Wu Taizong, Capon Robert J
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
Boehringer Ingelheim Animal Health, USA Inc., 1730 Olympic Drive, Athens, GA 30601, USA.
Antibiotics (Basel). 2024 Dec 17;13(12):1222. doi: 10.3390/antibiotics13121222.
BACKGROUND/OBJECTIVES: There is an urgent need for new and improved anthelmintics that are not constrained by existing resistance pathways and that can safeguard the health and welfare of animals.
An integrated platform of chemical, bioassay, and cultivation profiling applied to a library of microbes isolated from Australian livestock pasture soil was used to detect and guide the production, isolation, characterization, identification, and evaluation of new natural products with anthelmintic properties.
A global natural products social (GNPS) molecular network analysis of 110 Australian pasture-soil-derived microbial extracts prioritized for antiparasitic activity identified unique molecular families in the extract of sp. S4S-00185A06, a strain selectively active against microfilariae. UPLC-DAD analysis identified metabolites with unique UV-vis chromophores and unprecedented molecular formulas. A chemical investigation of sp. S4S-00185A06 yielded goondicones A-H (-) as new examples of a rare class of spiro-isoindolinones, with structures assigned on the basis of detailed spectroscopic analysis, ECD calculations, and biosynthetic considerations.
While goondicones - exhibit little to no in vitro inhibitory activity against Gram-positive, Gram-negative, and/or fungal pathogens, human carcinoma cells, or the livestock gastrointestinal parasite L1-L3 larvae, and (and, to a lesser extent, ) inhibit the motility of heartworm microfilaria (IC 10-11 μM). A structure activity relationship analysis based on the co-metabolites - suggests that (i) an 8-OH is preferable to 8-oxo moiety, (ii) 20-NMe and 3-OH moieties are essential, and (iii) C-9 epimerization exerts no discernible impact on in vitro potency.
背景/目的：迫切需要新的、改良的驱虫药，这些药物不受现有抗性途径的限制，能够保障动物的健康和福祉。
采用化学、生物测定和培养分析的综合平台，应用于从澳大利亚牲畜牧场土壤中分离的微生物文库，以检测和指导具有驱虫特性的新天然产物的生产、分离、表征、鉴定和评估。
对110种优先考虑抗寄生虫活性的澳大利亚牧场土壤来源的微生物提取物进行全球天然产物社会（GNPS）分子网络分析，确定了对微丝蚴具有选择性活性的菌株sp. S4S-00185A06提取物中的独特分子家族。超高效液相色谱-二极管阵列检测（UPLC-DAD）分析确定了具有独特紫外-可见发色团和前所未有的分子式的代谢产物。对sp. S4S-00185A06的化学研究产生了贡迪酮A-H（-），作为一类罕见的螺异吲哚酮的新实例，其结构基于详细的光谱分析、电子圆二色（ECD）计算和生物合成考虑确定。
虽然贡迪酮-对革兰氏阳性、革兰氏阴性和/或真菌病原体、人类癌细胞或牲畜胃肠道寄生虫L1-L3幼虫几乎没有体外抑制活性，且（以及在较小程度上）抑制犬恶丝虫微丝蚴的运动（IC为10-11 μM）。基于共代谢产物的构效关系分析表明：（i）8-羟基比8-氧代部分更可取；（ii）20-NMe和3-羟基部分是必不可少的；（iii）C-9差向异构化对体外效力没有明显影响。
