Paunkov Ana, Sóki József, Leitsch David
Institute for Specific Prophylaxis and Tropical Medicine Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.
Faculty of Medicine, Institute of Medical Microbiology, University of Szeged, Szeged, Hungary.
Front Microbiol. 2022 Jun 9;13:898453. doi: 10.3389/fmicb.2022.898453. eCollection 2022.
is a commensal of the human gut but can also cause severe infections when reaching other body sites, especially after surgery or intestinal trauma. is an anaerobe innately susceptible to metronidazole, a 5-nitroimidazole drug that is prescribed against the majority of infections caused by anaerobic bacteria. In most of the cases, metronidazole treatment is effective but a fraction of . is resistant to even very high doses of metronidazole. Metronidazole resistance is still poorly understood, but the so-called genes have been described as resistance determinants. They have been suggested to encode nitroreductases which reduce the nitro group of metronidazole to a non-toxic aminoimidazole. More recent research, however, showed that expression levels of genes are widely independent of the degree of resistance observed. In the search for an alternative model for -mediated metronidazole resistance, we screened a strain carrying an episomal gene and its parental strain 638R without a gene for physiological differences. Indeed, the 638R daughter strain with the gene had a far higher pyruvate-ferredoxin oxidoreductase (PFOR) activity than the parental strain. High PFOR activity was also observed in metronidazole-resistant clinical isolates, either with or without a gene. Moreover, the strain carrying a gene fully retained PFOR activity and other enzyme activities such as thioredoxin reductase (TrxR) after resistance had been induced. In the parental strain 638R, these were lost or very strongly downregulated during the development of resistance. Further, after induction of high-level metronidazole resistance, parental strain 638R was highly susceptible to oxygen whereas the daughter strain with a gene was hardly affected. Ensuing RT-qPCR measurements showed that a pathway for iron import hemin uptake is downregulated in 638R with induced resistance but not in the resistant daughter strain. We propose that primes . toward an alternative pathway of metronidazole resistance by enabling the preservation of normal iron levels in the cell.
是人体肠道的共生菌，但当到达身体其他部位时也可引起严重感染，尤其是在手术后或肠道创伤后。是一种天生对甲硝唑敏感的厌氧菌，甲硝唑是一种5-硝基咪唑类药物，用于治疗大多数由厌氧菌引起的感染。在大多数情况下，甲硝唑治疗是有效的，但有一部分……对甚至非常高剂量的甲硝唑耐药。甲硝唑耐药性仍了解甚少，但所谓的……基因已被描述为耐药决定因素。有人认为它们编码硝基还原酶，可将甲硝唑的硝基还原为无毒的氨基咪唑。然而，最近的研究表明，……基因的表达水平与观察到的耐药程度广泛无关。在寻找介导甲硝唑耐药性的替代模型时，我们筛选了携带附加型……基因的菌株及其没有……基因的亲本菌株638R的生理差异。确实，带有……基因的638R子代菌株的丙酮酸-铁氧化还原蛋白氧化还原酶（PFOR）活性远高于亲本菌株。在有或没有……基因的甲硝唑耐药临床分离株中也观察到高PFOR活性。此外，携带……基因的菌株在诱导耐药后完全保留了PFOR活性和其他酶活性，如硫氧还蛋白还原酶（TrxR）。在亲本菌株638R中，这些在耐药性发展过程中丧失或非常强烈地下调。此外，在诱导高水平甲硝唑耐药后，亲本菌株638R对氧气高度敏感，而带有……基因的子代菌株几乎不受影响。随后的RT-qPCR测量表明，铁摄取途径——血红素摄取在诱导耐药的638R中下调，但在耐药的……子代菌株中没有下调。我们提出，……通过使细胞中正常铁水平得以保留，使……走向甲硝唑耐药的替代途径。
