Lu Junzhuo, Cheng Lei, Huang Yuyao, Jiang Yaling, Chu Chun-Hung, Peng Xian, Li Mingyun, Xu Hockin H K, Zhou Xuedong, Ren Biao
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
Front Microbiol. 2020 Jan 21;10:3102. doi: 10.3389/fmicb.2019.03102. eCollection 2019.
Bacterial persistence has become a worldwide health problem due to its ability to cause the recalcitrance and relapse of infections. The existence of bacterial persistence and their possible mechanisms have been widely reported. However, the following regrowth of persister cells is not clear although the awakening of dormant surviving persisters is the key to reinitialize bacterial infection. In this study, we investigated the growth character and cariogenic virulence during the recovery of drug-tolerant persister cells induced by a novel quaternary ammonium: dimethylaminododecyl methacrylate (DMADDM). A remarkable lag phase was observed in persisters when regrew at the first 24 h compared to normal cells. During the entire recovery state, persisters are metabolically active to increase the production of both water-soluble and water-insoluble glucan. The shortage of cell number in persisters resulted in the decrease of lactic acid production, but persisters gradually recovered the normal acid production ability after 72 h. The up-regulated expression of and was in line with comDE circuit and consistent with the virulence change during the regrowth stage. Our findings proved that lethal dosages of DMADDM induced drug-tolerant persisters in biofilm, which had a prolonged lag phase and elevated cariogenic virulence during regrowth. The recovery and elevated virulence of persisters were regulated by quorum-sensing and VicRK pathway. This alarmed the elevated cariogenicity of persisters and highlighted the critical requirement for the drug-tolerance evaluation when developing new oral antimicrobial agents. To the best of our knowledge, we characterized the regrowth and cariogenic virulence variation of persisters induced by quaternary ammonium for the first time. Our findings suggest that persisters with the elevated cariogenic virulence during their regrowth stage highlighted the need of new strategy to overcome bacterial persistence. Meanwhile, the prolonged lag phase and the involvement of quorum-sensing system in the regrowth of persisters may provide the potential targets.
由于细菌持久性能够导致感染的顽固性和复发，它已成为一个全球性的健康问题。细菌持久性的存在及其可能的机制已被广泛报道。然而，尽管休眠存活的持留菌的苏醒是重新引发细菌感染的关键，但持留菌细胞随后的再生长情况尚不清楚。在本研究中，我们调查了由一种新型季铵盐：甲基丙烯酸十二烷基二甲胺酯（DMADDM）诱导产生的耐药物持留菌细胞恢复过程中的生长特性和致龋毒力。与正常细胞相比，持留菌在前24小时重新生长时观察到明显的延迟期。在整个恢复状态期间，持留菌代谢活跃，水溶性和水不溶性葡聚糖的产量均增加。持留菌细胞数量的短缺导致乳酸产量下降，但持留菌在72小时后逐渐恢复正常的产酸能力。和的表达上调与comDE信号通路一致，且与再生长阶段的毒力变化相符。我们的研究结果证明，致死剂量的DMADDM在生物膜中诱导产生耐药物持留菌，这些持留菌在再生长过程中具有延长的延迟期和升高的致龋毒力。持留菌的恢复和毒力升高受群体感应和VicRK信号通路调控。这警示了持留菌致龋性的升高，并突出了开发新型口腔抗菌剂时进行耐药物性评估的关键需求。据我们所知，我们首次对季铵盐诱导的持留菌的再生长和致龋毒力变化进行了表征。我们的研究结果表明，持留菌在其再生长阶段致龋毒力升高，这凸显了需要新的策略来克服细菌持久性。同时，持留菌延长的延迟期以及群体感应系统参与其再生长过程可能提供了潜在靶点。
