Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom.
Department of Physics and Astronomy, University of Sheffield, Sheffield, United Kingdom.
PLoS Biol. 2024 Aug 15;22(8):e3002741. doi: 10.1371/journal.pbio.3002741. eCollection 2024 Aug.
Clostridioides difficile is an important human pathogen, for which there are very limited treatment options, primarily the glycopeptide antibiotic vancomycin. In recent years, vancomycin resistance has emerged as a serious problem in several gram-positive pathogens, but high-level resistance has yet to be reported for C. difficile, although it is not known if this is due to constraints upon resistance evolution in this species. Here, we show that resistance to vancomycin can evolve rapidly under ramping selection but is accompanied by fitness costs and pleiotropic trade-offs, including sporulation defects that would be expected to severely impact transmission. We identified 2 distinct pathways to resistance, both of which are predicted to result in changes to the muropeptide terminal D-Ala-D-Ala that is the primary target of vancomycin. One of these pathways involves a previously uncharacterised D,D-carboxypeptidase, expression of which is controlled by a dedicated two-component signal transduction system. Our findings suggest that while C. difficile is capable of evolving high-level vancomycin resistance, this outcome may be limited clinically due to pleiotropic effects on key pathogenicity traits. Moreover, our data identify potential mutational routes to resistance that should be considered in genomic surveillance.
艰难梭菌是一种重要的人类病原体，其治疗选择非常有限，主要是糖肽类抗生素万古霉素。近年来，万古霉素耐药性已成为几种革兰氏阳性病原体的严重问题，但尚未报道艰难梭菌出现高水平耐药性，尽管尚不清楚这是否是由于该物种对耐药性进化的限制。在这里，我们表明，在逐步选择下，对万古霉素的耐药性可以迅速进化，但伴随着适应性成本和多效性权衡，包括可能严重影响传播的孢子形成缺陷。我们确定了 2 种不同的耐药途径，这两种途径都可能导致万古霉素的主要靶标 muropeptide 末端 D-Ala-D-Ala 发生变化。其中一种途径涉及一种以前未被描述的 D,D-羧肽酶，其表达受专门的双组分信号转导系统控制。我们的研究结果表明，尽管艰难梭菌能够进化出高水平的万古霉素耐药性，但由于对关键致病性特征的多效性影响，这种结果在临床上可能受到限制。此外，我们的数据确定了潜在的耐药突变途径，在基因组监测中应加以考虑。
