Health Sciences North Research Institute, Sudbury, Ontario, Canada.
Biomolecular Sciences Program, Laurentian University, Sudbury, Ontario, Canada.
PLoS One. 2021 Sep 7;16(9):e0257143. doi: 10.1371/journal.pone.0257143. eCollection 2021.
Clostridioides difficile infection (CDI) is the primary cause of hospital-acquired diarrhea, and responsible for over 500,000 enteric infections a year in the United States alone. Although most patients with CDI are successfully treated with metronidazole or vancomycin, the high rate of recurrence is still a serious problem, in which case these antibiotics are usually not very effective. The primary objective of this research is to develop a potentially effective therapeutic agent against C. difficile that are resistant to metronidazole or vancomycin. The susceptibility to metronidazole and vancomycin was examined with 194 C. difficile clinical isolates. Sixty of these isolates chosen based on a variety of criteria were examined for their susceptibility against the 4-chloro-1-piperidin-1ylmethyl-1H-indole-2,3-dione compound (Raja 42), a novel isatin-benzothiazole analogue containing a gamma-lactam structure, as we previously found that this novel compound is effective against a variety of different bacteria. Most of the 60 isolates were resistant to ceftriaxone and ciprofloxacin, raising the possibility that they might have been exposed previously to these or structurally similar antibiotics (e.g., β-lactam and quinolone compounds). Among the isolates, 48 (80%) and 54 (90%) were susceptible to metronidazole and vancomycin, respectively. Raja 42 was found to be effective against most of the isolates, especially so against metronidazole-resistant C. difficile. Most importantly, five isolates that show resistance to metronidazole and vancomycin were sensitive to Raja 42. Thus, Raja 42, a gamma lactam antibiotic, has the potential to effectively control C. difficile strains that are resistant to metronidazole and vancomycin.
艰难梭菌感染（CDI）是医院获得性腹泻的主要原因，仅在美国，每年就有超过 50 万例肠道感染是由艰难梭菌引起的。虽然大多数艰难梭菌感染患者用甲硝唑或万古霉素治疗都能成功，但复发率仍然是一个严重的问题，在这种情况下，这些抗生素通常效果不佳。本研究的主要目的是开发一种针对甲硝唑或万古霉素耐药的艰难梭菌的潜在有效治疗药物。用 194 株艰难梭菌临床分离株检测甲硝唑和万古霉素的敏感性。根据各种标准选择其中 60 株进行研究，以检测其对 4-氯-1-哌啶-1-基甲基-1H-吲哚-2,3-二酮化合物（Raja 42）的敏感性，这是一种新型的色氨酸-苯并噻唑类似物，含有γ-内酰胺结构，因为我们之前发现这种新型化合物对多种不同的细菌都有效。这 60 株分离株中的大多数对头孢曲松和环丙沙星耐药，这表明它们以前可能接触过这些或结构相似的抗生素（例如β-内酰胺和喹诺酮类化合物）。在这些分离株中，分别有 48（80%）和 54（90%）对甲硝唑和万古霉素敏感。结果发现 Raja 42 对大多数分离株都有效，特别是对甲硝唑耐药的艰难梭菌。最重要的是，对甲硝唑和万古霉素耐药的 5 株分离株对 Raja 42 敏感。因此，Raja 42，一种γ-内酰胺抗生素，具有有效控制对甲硝唑和万古霉素耐药的艰难梭菌菌株的潜力。
