Department of Chemistry, Aarhus University, Aarhus, Denmark.
Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark.
Microbiol Spectr. 2023 Aug 17;11(4):e0062523. doi: 10.1128/spectrum.00625-23. Epub 2023 Jun 8.
Polyether ionophores are complex natural products known to transport various cations across biological membranes. While several members of this family are used in agriculture (e.g., as anti-coccidiostats) and have potent antibacterial activity, they are not currently being pursued as antibiotics for human use. Polyether ionophores are typically grouped as having similar functions, despite the fact that they significantly differ in structure; for this reason, how their structure and activity are related remains unclear. To determine whether certain members of the family constitute particularly interesting springboards for in-depth investigations and future synthetic optimization, we conducted a systematic comparative study of eight different polyether ionophores for their potential as antibiotics. This includes clinical isolates from bloodstream infections and studies of the compounds' effects on bacterial biofilms and persister cells. We uncover distinct differences within the compound class and identify the compounds lasalocid, calcimycin, and nanchangmycin as having particularly interesting activity profiles for further development. Polyether ionophores are complex natural products used in agriculture as anti-coccidiostats in poultry and as growth promoters in cattle, although their precise mechanism is not understood. They are widely regarded as antimicrobials against Gram-positive bacteria and protozoa, but fear of toxicity has so far prevented their use in humans. We show that ionophores generally have very different effects on Staphylococcus aureus, both in standard assays and in more complex systems such as bacterial biofilms and persister cell populations. This will allow us to focus on the most interesting compounds for future in-depth investigations and synthetic optimizations.
多醚离子载体是一类复杂的天然产物，已知能够将各种阳离子转运穿过生物膜。虽然该家族的几个成员被用于农业（例如，作为抗球虫药）并且具有很强的抗菌活性，但它们目前并未被用作人类使用的抗生素。尽管多醚离子载体在结构上有很大的差异，但它们通常被归为具有相似功能的一类，因此它们的结构和活性之间的关系仍不清楚。为了确定该家族的某些成员是否构成特别有趣的跳板，以进行深入研究和未来的合成优化，我们对 8 种不同的多醚离子载体进行了系统的比较研究，以评估它们作为抗生素的潜力。这包括来自血流感染的临床分离株的研究，以及研究化合物对细菌生物膜和持久细胞的影响。我们在该化合物类别中发现了明显的差异，并确定了化合物 lasalocid、calcimycin 和 nanchangmycin 具有特别有趣的活性谱，可进一步开发。
多醚离子载体是农业中使用的复杂天然产物，作为禽类的抗球虫药和牛的生长促进剂，尽管其确切机制尚不清楚。它们被广泛认为是对抗革兰氏阳性菌和原生动物的抗菌药物，但对毒性的担忧阻止了它们在人类中的应用。我们表明，离子载体通常对金黄色葡萄球菌有非常不同的影响，无论是在标准测定中还是在更复杂的系统中，如细菌生物膜和持久细胞群体。这将使我们能够专注于最有趣的化合物，以进行未来的深入研究和合成优化。
