Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
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DOI：
10.1128/msphere.00157-20
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发表时间：
2020-03-01
期刊：
影响因子：
4.8
通讯作者：
Cook, Gregory M.
中科院分区：
文献类型：
--
作者：
Harbison-Price, Nichaela;Ferguson, Scott A.;Cook, Gregory M.
在全球范围内，用于食用动物的抗菌药物比用于人类的抗菌药物更多，在面临抗生素耐药性（AMR）上升的情况下，广泛使用医学上重要的人类抗菌药物对公共卫生构成了重大威胁。新型离子载体（一类专门用于动物的抗菌剂）的开发有望成为替代或减少兽医实践中必需的人类抗菌剂的策略。PBT 2是一种锌离子载体，最近证实对几种革兰氏阳性病原体具有抗菌活性，但其潜在的作用机制尚不清楚。在这里，我们研究了PBT 2的杀菌机制，在牛乳腺炎引起的病原体，链球菌。在这项工作中，我们表明，PBT 2作为一个Zn 2 +/H+离子载体，交换细胞外锌细胞内质子的电中性过程，导致细胞锌积累。锌的积累伴随着锰的消耗和活性氧（ROS）的产生。PBT 2抑制锰依赖性超氧化物歧化酶SodA的活性，从而损害氧化应激保护。我们认为PBT 2介导的S.维生素E通过多种杀菌机制导致致死性：产生毒性ROS和损害锰依赖性抗氧化功能。总的来说，这些数据表明PBT 2代表了一类新的抗菌离子载体，能够靶向细菌金属离子稳态和细胞氧化还原平衡。我们建议，这种新的和多靶点机制的PBT 2使交叉耐药性的发展，以医学上重要的antimicrobials impossible.IMPORTANCE更多的抗菌药物用于食品生产动物比人类，和广泛使用的医学上重要的人类抗菌药物构成了重大的公共卫生威胁，在面对不断上升的抗菌药物耐药性。因此，消除人用药物和兽药之间的抗菌交叉具有重大意义。不幸的是，开发新的抗菌剂是一个昂贵的高风险过程，充满了困难。化学制剂的再利用为这一问题提供了解决方案，虽然许多化学制剂最初并不是作为抗菌剂开发的，但它们已在临床试验中被证明是安全的。PBT 2是一种锌离子载体，是一种符合安全标准的实验性治疗药物，但未能通过针对阿尔茨海默病和亨廷顿病的疗效检查点。最近发现PBT 2具有有效的抗微生物活性，尽管细菌细胞死亡的机制尚未解决。在这项工作中，我们表明PBT 2具有多种抗菌作用机制，使PBT 2耐药性的发展不太可能。
Globally, more antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance (AMR). The development of novel ionophores, a class of antimicrobials used exclusively in animals, holds promise as a strategy to replace or reduce essential human antimicrobials in veterinary practice. PBT2 is a zinc ionophore with recently demonstrated antibacterial activity against several Gram-positive pathogens, although the underlying mechanism of action is unknown. Here, we investigated the bactericidal mechanism of PBT2 in the bovine mastitis-causing pathogen, Streptococcus uberis. In this work, we show that PBT2 functions as a Zn2+/H+ ionophore, exchanging extracellular zinc for intracellular protons in an electroneutral process that leads to cellular zinc accumulation. Zinc accumulation occurs concomitantly with manganese depletion and the production of reactive oxygen species (ROS). PBT2 inhibits the activity of the manganese-dependent superoxide dismutase, SodA, thereby impairing oxidative stress protection. We propose that PBT2-mediated intracellular zinc toxicity in S. uberis leads to lethality through multiple bactericidal mechanisms: the production of toxic ROS and the impairment of manganese-dependent antioxidant functions. Collectively, these data show that PBT2 represents a new class of antibacterial ionophores capable of targeting bacterial metal ion homeostasis and cellular redox balance. We propose that this novel and multitarget mechanism of PBT2 makes the development of cross-resistance to medically important antimicrobials unlikely.IMPORTANCE More antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance. Therefore, the elimination of antimicrobial crossover between human and veterinary medicine is of great interest. Unfortunately, the development of new antimicrobials is an expensive high-risk process fraught with difficulties. The repurposing of chemical agents provides a solution to this problem, and while many have not been originally developed as antimicrobials, they have been proven safe in clinical trials. PBT2, a zinc ionophore, is an experimental therapeutic that met safety criteria but failed efficacy checkpoints against both Alzheimer's and Huntington's diseases. It was recently found that PBT2 possessed potent antimicrobial activity, although the mechanism of bacterial cell death is unresolved. In this body of work, we show that PBT2 has multiple mechanisms of antimicrobial action, making the development of PBT2 resistance unlikely.