BceAB-type antibiotic resistance transporters appear to act by target protection of cell wall synthesis
BceAB-type antibiotic resistance transporters appear to act by target protection of cell wall synthesis
复制标题
BceAB 型抗生素抗性转运蛋白似乎通过细胞壁合成的目标保护发挥作用
DOI：
10.1101/835702
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Kobras C
中科院分区：
文献类型：
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作者：
Kobras C
细菌对细胞壁活性抗菌肽的抗性通常由转运蛋白介导。在低GC含量的革兰氏阳性细菌中，这种转运蛋白的一种常见类型是BceAB样系统，其经常提供对靶向细胞壁合成的脂质II循环的中间体的肽抗生素的高水平抗性。然而，转运蛋白如何保护细胞免受在细胞表面活跃的药物的影响，这给研究人员带来了一个难题。已经讨论了多种理论，从从膜上去除肽和药物内化降解到去除细胞靶点而不是药物本身。为了解决这个备受争议的问题，我们在这里研究了枯草芽孢杆菌的转运蛋白BceAB的作用模式。我们表明，它不吸收或输入其底物抗生素杆菌肽。此外，我们提出的证据表明，驱动运输活动的关键因素不是药物本身，而是细胞中药物-靶标复合物的浓度。我们的研究结果，加上以前报道的结果，使我们提出，BceAB型转运蛋白的作用，暂时释放脂质II循环中间体的抗菌肽的抑制性抓地力，从而提供通过靶向保护细胞壁合成的阻力。迄今为止，仅报道了针对具有细胞内靶标（如核糖体）的抗生素的抗性的靶标保护。然而，这一机制为使用转运蛋白作为革兰氏阳性菌中细胞壁活性抗生素的抗性决定因素提供了合理的解释，其中细胞壁合成缺乏外膜的额外保护。
Resistance against cell wall-active antimicrobial peptides in bacteria is often mediated by transporters. In low-GC-content Gram-positive bacteria, a common type of such transporters is BceAB-like systems, which frequently provide high-level resistance against peptide antibiotics that target intermediates of the lipid II cycle of cell wall synthesis. How a transporter can offer protection from drugs that are active on the cell surface, however, has presented researchers with a conundrum. Multiple theories have been discussed, ranging from removal of the peptides from the membrane and internalization of the drug for degradation to removal of the cellular target rather than the drug itself. To resolve this much-debated question, we here investigated the mode of action of the transporter BceAB of Bacillus subtilis. We show that it does not inactivate or import its substrate antibiotic bacitracin. Moreover, we present evidence that the critical factor driving transport activity is not the drug itself but instead the concentration of drug-target complexes in the cell. Our results, together with previously reported findings, lead us to propose that BceAB-type transporters act by transiently freeing lipid II cycle intermediates from the inhibitory grip of antimicrobial peptides and thus provide resistance through target protection of cell wall synthesis. Target protection has so far only been reported for resistance against antibiotics with intracellular targets, such as the ribosome. However, this mechanism offers a plausible explanation for the use of transporters as resistance determinants against cell wall-active antibiotics in Gram-positive bacteria where cell wall synthesis lacks the additional protection of an outer membrane.