Peptidylarginine Deiminase Inhibitors Reduce Bacterial Membrane Vesicle Release and Sensitize Bacteria to Antibiotic Treatment
Peptidylarginine Deiminase Inhibitors Reduce Bacterial Membrane Vesicle Release and Sensitize Bacteria to Antibiotic Treatment
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DOI：
10.3389/fcimb.2019.00227
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发表时间：
2019-06-27
影响因子：
5.7
通讯作者：
Inal, Jameel M.
中科院分区：
文献类型：
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作者：
Kosgodage, Uchini S.;Matewele, Paul;Inal, Jameel M.
外膜和膜囊泡（OMV/MV）从细菌中释放出来，参与细胞通讯、生物膜形成和宿主-病原体相互作用。肽精氨酸脱亚胺酶（Peptidylarginine de亚胺酶，PADs）是一种系统发育上保守的酶，它催化蛋白质的翻译后脱亚胺/瓜氨酸化，引起靶蛋白的结构和功能改变。pad还在真核细胞外囊泡释放调控中发挥重要作用。在这里，我们展示了pad介导的OMV/MV在细菌中释放的系统发育保守途径，并描述了大肠杆菌中的去亚胺/瓜氨酸化蛋白及其衍生的OMV/MV。此外，我们发现PAD抑制剂可以有效地减少革兰氏阴性和革兰氏阳性细菌的OMV/MV释放。重要的是，这导致大肠杆菌和金黄色葡萄球菌对一系列抗生素的敏感性增强。我们的研究结果揭示了应用药理学OMV/ mv抑制来降低抗生素耐药性的新策略。
Outer membrane and membrane vesicles (OMV/MV) are released from bacteria and participate in cell communication, biofilm formation and host-pathogen interactions. Peptidylarginine deiminases (PADs) are phylogenetically conserved enzymes that catalyze post-translational deimination/citrullination of proteins, causing structural and functional changes in target proteins. PADs also play major roles in the regulation of eukaryotic extracellular vesicle release. Here we show phylogenetically conserved pathways of PAD-mediated OMV/MV release in bacteria and describe deiminated/citrullinated proteins in E. coli and their derived OMV/MVs. Furthermore, we show that PAD inhibitors can be used to effectively reduce OMV/MV release, both in Gram-negative and Gram-positive bacteria. Importantly, this resulted in enhanced antibiotic sensitivity of both E. coli and S. aureus to a range of antibiotics tested. Our findings reveal novel strategies for applying pharmacological OMV/MV-inhibition to reduce antibiotic resistance.