Switch Laboratory, VIB Center for Brain and Disease Research, Herestraat 49, 3000, Leuven, Belgium.
Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
Nat Commun. 2023 Sep 9;14(1):5571. doi: 10.1038/s41467-023-41191-z.
There is an arms race between beta-lactam antibiotics development and co-evolving beta-lactamases, which provide resistance by breaking down beta-lactam rings. We have observed that certain beta-lactamases tend to aggregate, which persists throughout their evolution under the selective pressure of antibiotics on their active sites. Interestingly, we find that existing beta-lactamase active site inhibitors can act as molecular chaperones, promoting the proper folding of these resistance factors. Therefore, we have created Pept-Ins, synthetic peptides designed to exploit the structural weaknesses of beta-lactamases by causing them to misfold into intracellular inclusion bodies. This approach restores sensitivity to a wide range of beta-lactam antibiotics in resistant clinical isolates, including those with Extended Spectrum variants that pose significant challenges in medical practice. Our findings suggest that targeted aggregation of resistance factors could offer a strategy for identifying molecules that aid in addressing the global antibiotic resistance crisis.
β-内酰胺抗生素的开发与协同进化的β-内酰胺酶之间存在着一场军备竞赛，后者通过破坏β-内酰胺环来提供耐药性。我们观察到某些β-内酰胺酶倾向于聚集，在抗生素对其活性部位的选择性压力下，这种聚集在它们的进化过程中一直存在。有趣的是，我们发现现有的β-内酰胺酶活性位点抑制剂可以作为分子伴侣，促进这些耐药因子的正确折叠。因此，我们创建了 Pept-Ins，这是一种合成肽，旨在通过使β-内酰胺酶错误折叠成细胞内包含体来利用其结构弱点。这种方法恢复了对广泛的β-内酰胺抗生素的敏感性，包括那些具有扩展谱变体的抗生素，这些变体在医疗实践中构成了重大挑战。我们的研究结果表明，针对耐药因子的靶向聚集可能为寻找有助于解决全球抗生素耐药性危机的分子提供一种策略。
