Metal complexes and conjugation: Harnessing the power of cobalt complexes to curtail plasmid transfer
Metal complexes and conjugation: Harnessing the power of cobalt complexes to curtail plasmid transfer
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金属络合物和缀合：利用钴络合物的力量来减少质粒转移
DOI：
10.1101/2023.11.24.568573
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Alav I
中科院分区：
文献类型：
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作者：
Alav I
背景抗菌药物耐药基因（Antimicrobial resistance gene，ARG），如超广谱β-内酰胺酶（extended spectrum β-lactamase，ESBL）和碳青霉烯酶（carbapenemase，Carbapenemase）基因，通常携带在质粒上。疟原虫可以在细菌之间传播，在全球范围内传播，并引起临床上重要的耐药性。因此，靶向质粒可以降低ARG的流行率，并恢复现有抗生素的功效。在这里，我们评估了四个以前的特点双（N-吡啶酰胺基）钴（II）配合物的接合转移的质粒inEscherichia coliandKlebsiella pneumoniae.MethodsLiquid肉汤和固体琼脂接合试验的效果被用来测量复杂的活动四个质粒inE。杆菌此外，测试了钴络合物对编码pCTgfp质粒的荧光标记的超广谱β-内酰胺酶在E.大肠杆菌和编码碳青霉烯酶的pKpQILgfp质粒inK.结果钴配合物的抗菌药物敏感性测试显示没有抗菌活性。钴配合物显著降低RP 4、R6 K和R388质粒在E. coli和pKpQILgfp在K.没有影响pKM 101的接合转移或荧光标记的pCT在E中的传递。杆菌钴络合物对质粒持久性没有影响，这表明他们的目标接合，而不是质粒prevalence.ConclusionsTo最好的我们所知，这是第一个研究报告减少临床相关的质粒与钴络合物的传输。这些钴配合物对哺乳动物细胞没有细胞毒性，也没有抗菌性，因此它们可以被优化并用作缀合抑制剂，以减少动物和人类中AMR和/或毒力基因的流行。一些最有问题的耐药基因携带在遗传元件上，称为质粒，可以在细菌之间传播。虽然我们对细菌之间基因转移的机制和驱动因素的了解正在增加，但我们缺乏有效的工具来减缓/控制这些过程。在这里，我们首次证明新型钴基化合物对大肠杆菌的一个子集具有抗质粒活性。大肠杆菌质粒，并在K.肺炎携带临床碳青霉烯类耐药质粒，而不影响质粒维持。这一发现为控制革兰氏阴性菌内基因转移的潜在策略奠定了基础，这对AMR和毒力具有影响。
BackgroundAntimicrobial resistance genes (ARG), such as extended spectrum β-lactamase (ESBL) and carbapenemase genes, are commonly carried on plasmids. Plasmids can transmit between bacteria, disseminate globally, and cause clinically important resistance. Therefore, targeting plasmids could reduce ARG prevalence, and restore the efficacy of existing antibiotics. Here, we assessed the effect of four previously characterised bis(N-picolinamido)cobalt(II) complexes on the conjugative transfer of plasmids inEscherichia coliandKlebsiella pneumoniae.MethodsLiquid broth and solid agar conjugation assays were used to measure complex activity on four plasmids inE. coli. Additionally, the effect of cobalt complexes was tested on the transmission of the fluorescently tagged extended spectrum β-lactamase encoding pCTgfpplasmid inE. coliand carbapenemase encoding pKpQILgfpplasmid inK. pneumoniae, using flow cytometry.ResultsAntimicrobial susceptibility testing of cobalt complexes revealed no antibacterial activity. The cobalt complexes significantly reduced conjugative transfer of RP4, R6K, and R388 plasmids on solid agar inE. coliand pKpQILgfptransmission inK. pneumoniae.None affected conjugative transfer of pKM101 or transmission of fluorescently tagged pCT inE. coli. The cobalt complexes had no effect on plasmid persistence, suggesting that they target conjugation rather than plasmid prevalence.ConclusionsTo the best of our knowledge, this is the first study to report reduced transmission of clinically relevant plasmids with cobalt complexes. These cobalt complexes are not cytotoxic towards mammalian cells and are not antibacterial, therefore they could be optimised and employed as conjugation inhibitors to reduce prevalence of AMR and/or virulence genes in animals and humans.SignificanceAntimicrobial resistance is a growing problem that poses a significant threat to modern medicine. Some of the most problematic resistance genes are carried on genetic elements, called plasmids, that can spread between bacteria. While our understanding of the mechanisms and drivers of gene transfer amongst bacteria is increasing, we lack effective tools to slow down/control these processes. Here we demonstrate for the first time that novel cobalt-based compounds have anti-plasmid activity on a subset ofE. coliplasmids, and are extremely potent inK. pneumoniaecarrying a clinical carbapenem-resistance plasmid, without impacting plasmid maintenance. This finding forms the foundations of a potential strategy to control the transfer of genes within Gram-negative bacteria, which has implications for AMR and virulence.