Toxin Induction or Inhibition of Transcription or Translation Posttreatment Increases Persistence to Fluoroquinolones.
Toxin Induction or Inhibition of Transcription or Translation Posttreatment Increases Persistence to Fluoroquinolones.
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DOI：
10.1128/mbio.01983-21
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Brynildsen MP
中科院分区：
文献类型：
--
作者：
Lemma AS;Brynildsen MP
毒素-抗毒素模块在原核生物中广泛存在，并且毒素积累增加细菌对抗生素的耐受性的能力已经被充分记录。这种功能的传统模型意味着过量的毒素会阻止细菌生长，从而抑制抗生素靶向的过程，从而限制它们的腐败和随之而来的致命损害。该模型暗示毒素在治疗前和/或治疗期间对抗生素致死率产生影响，即使它们在治疗结束后也存在并起作用。鉴于最近的证据表明，抗生素治疗（恢复）后的时期是重要的生存与氟喹诺酮类（FQs）治疗的非生长细菌种群，我们分析了毒素在何种程度上影响细菌的生存在恢复期。与LdrD和MazF，毒素的I型和II型系统，分别控制积累发生后，FQ治疗的非生长培养物导致持久性显着增加。进一步的遗传学研究揭示了同源重组和核苷酸切除修复机制的重要作用。集中在野生型，我们没有观察到任何SOS诱导的毒素以这种方式发挥作用;然而，在野生型大肠杆菌和尿路致病性大肠杆菌中观察到类似的现象。当转录或翻译在FQ后恢复期受到抑制时，总的来说，这些数据揭示了毒素即使在治疗结束后也能阻碍FQ杀灭的能力，并表明如果细菌在治疗结束时不能容易地恢复翻译和生长，则非生长细菌的FQ治疗可能在很大程度上无效。
Toxin-antitoxin modules are widespread in prokaryotes, and the capacity of toxin accumulation to increase the tolerances of bacteria to antibiotics has been well documented. The conventional model for this functionality implies that an overabundance of toxin arrests bacterial growth, which inhibits processes targeted by antibiotics and thereby limits their corruption and the lethal damage that would ensue. Implicit in this model is that toxins exert their influence on antibiotic lethality before and/or during treatment, even though they are also present and functional after treatment concludes. Given recent evidence establishing that the period following antibiotic treatment (recovery) is important for the survival of nongrowing bacterial populations treated with fluoroquinolones (FQs), we assayed to what extent toxins influence bacterial survival during the recovery period. With both LdrD and MazF, toxins of type I and II systems, respectively, controlling accumulation to occur only after FQ treatment of nongrowing cultures resulted in significant increases in persisters. Further genetic investigation revealed important roles for homologous recombination and nucleotide excision repair machinery. Focusing on the wild type, we did not observe any SOS-induced toxin functioning in this manner; however, an analogous phenomenon was observed for wild-type Escherichia coli as well as uropathogenic E. coli (UPEC) when transcription or translation was inhibited during the post-FQ recovery period. Collectively, these data reveal the capacity of toxins to thwart FQ killing even after the treatment has concluded and show that FQ treatment of nongrowing bacteria can be rendered largely ineffective if bacteria cannot readily resume translation and growth at the conclusion of treatment.