Staphylococcus aureus Virulence Affected by an Alternative Nisin A Resistance Mechanism
Staphylococcus aureus Virulence Affected by an Alternative Nisin A Resistance Mechanism
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DOI：
10.1128/aem.02923-19
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发表时间：
2020-04-01
影响因子：
4.4
通讯作者：
Komatsuzawa, Hitoshi
中科院分区：
文献类型：
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作者：
Kawada-Matsuo, Miki;Watanabe, Atsuko;Komatsuzawa, Hitoshi
Nisin A是由乳酸乳球菌产生的细菌素，被广泛用作食品防腐剂。金黄色葡萄球菌具有BraRS-VraDE系统，该系统提供对低浓度乳链菌肽A的抗性。BraRS是诱导ABC转运蛋白VraDE表达的双组分系统。以前，我们分离出一个高度乳链菌肽A耐药菌株与增加VraDE的表达，由于突变的braRS。在本研究中，我们分离了S.金黄色葡萄球菌MW 2突变体具有BraRS-VraDE非依赖性乳链菌肽A抗性。这些突变体命名为SAN 2（S. aureus nisin resistant）和SAN 469在pmtR中具有突变，pmtR编码负责pmtABCD操纵子表达的转录调节因子。结果，这些突变体表现出PmtABCD的表达增加，PmtABCD是一种负责输出酚可溶性调节蛋白（PSM）的转运蛋白。突变体的表征揭示了它们对人β-防御素-3（hBD 3）和LL 37的易感性降低，这是先天免疫因子。此外，这些突变体显示出比原始MW 2菌株更高的溶血活性。此外，在小鼠菌血症模型中，SAN 2菌株表现出比原始MW 2菌株更低的存活率。这些结果表明，由于pmtR突变导致的pmtABCD表达增加是一种替代的乳链菌肽A抗性机制，也影响了S.重要性近来，耐药性细菌的出现导致了化疗的严重问题。此外，许多抗菌剂，如消毒剂和食品添加剂，也被广泛使用。因此，细菌有可能对某些抗菌剂产生耐药性。在这项研究中，我们调查了金黄色葡萄球菌是否可以成为耐乳酸链球菌素A，作为食品添加剂应用的细菌素之一。我们分离出一种高度耐乳链菌肽A的菌株SAN 2，该菌株显示Pmt蛋白表达增加，Pmt蛋白参与称为苯酚可溶性调节蛋白（PSM）的毒力因子的分泌。该菌株还显示出对人抗菌肽的敏感性降低和溶血活性增加。此外，SAN 2在小鼠菌血症模型中显示出增加的致死活性。我们的研究为获得对食品防腐剂的抗性可能调节S.金黄色葡萄球菌，这表明我们需要更加注意食物防腐剂与抗生素一起使用。
Nisin A is a bacteriocin produced by Lactococcus lactis and is widely used as a food preservative. Staphylococcus aureus has the BraRS-VraDE system that provides resistance against low concentrations of nisin A. BraRS is a two-component system that induces the expression of the ABC transporter VraDE. Previously, we isolated a highly nisin A-resistant strain with increased VraDE expression due to a mutation in braRS. In this study, we isolated S. aureus MW2 mutants with BraRS-VraDE-independent nisin A resistance. These mutants, designated SAN2 (S. aureus nisin resistant) and SAN469, had a mutation in pmtR, which encodes a transcriptional regulator responsible for the expression of the pmtABCD operon. As a result, these mutants exhibited increased expression of PmtABCD, a transporter responsible for the export of phenol-soluble modulin (PSM). Characterization of the mutants revealed that they have decreased susceptibility to human beta-defensin-3 (hBD3) and LL37, which are innate immune factors. Additionally, these mutants showed higher hemolytic activity than the original MW2 strain. Furthermore, in a mouse bacteremia model, the SAN2 strain exhibited a lower survival rate than the original MW2 strain. These results indicate that the increased expression of pmtABCD due to a pmtR mutation is an alternative nisin A resistance mechanism that also affects virulence in S. aureus.IMPORTANCE Recently, the emergence of antibiotic-resistant bacteria has resulted in serious problems for chemotherapy. In addition, many antibacterial agents, such as disinfectants and food additives, are widely used. Therefore, there is a possibility that bacteria are becoming resistant to some antibacterial agents. In this study, we investigated whether Staphylococcus aureus can become resistant to nisin A, one of the bacteriocins applied as a food additive. We isolated a highly nisin A-resistant strain designated SAN2 that displayed increased expression of Pmt proteins, which are involved in the secretion of virulence factors called phenol-soluble modulins (PSMs). This strain also showed decreased susceptibility to human antimicrobial peptides and increased hemolytic activity. In addition, SAN2 showed increased lethal activity in a mouse bacteremia model. Our study provides new insights into the possibility that the acquisition of resistance against food preservatives may modulate virulence in S. aureus, suggesting that we need to pay more attention to the use of food preservatives together with antibiotics.