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.
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.
Cell Chem Biol. 2021 Apr 15;28(4):524-536.e4. doi: 10.1016/j.chembiol.2020.12.008. Epub 2021 Jan 11.
Aggregation can be selectively induced by aggregation-prone regions (APRs) contained in the target proteins. Aggregation-inducing antimicrobial peptides (Pept-ins) contain sequences homologous to APRs of target proteins and exert their bactericidal effect by causing aggregation of a large number of proteins. To better understand the mechanism of action of Pept-ins and the resistance mechanisms, we analyzed the phenotypic, lipidomic, and transcriptomic as well as genotypic changes in laboratory-derived Pept-in-resistant E. coli mutator cells. The analysis showed that the Pept-in resistance mechanism is dominated by a decreased Pept-in uptake, in both laboratory-derived mutator cells and clinical isolates. Our data indicate that Pept-in uptake involves an electrostatic attraction between the Pept-in and the bacterial membrane and follows a complex mechanism potentially involving many transporters. Furthermore, it seems more challenging for bacteria to become resistant toward Pept-ins that are less dependent on electrostatic attraction for uptake, suggesting that future Pept-ins should be selected for this property.
聚集可以通过目标蛋白中富含聚集的区域（APR）来选择性诱导。聚集诱导型抗菌肽（Pept-ins）包含与目标蛋白的 APR 同源的序列，并通过引起大量蛋白质的聚集来发挥其杀菌作用。为了更好地了解 Pept-ins 的作用机制和耐药机制，我们分析了实验室衍生的 Pept-in 耐药大肠杆菌突变体细胞的表型、脂质组学、转录组学以及基因型变化。分析表明，Pept-in 耐药机制主要是通过减少 Pept-in 的摄取，这在实验室衍生的突变体细胞和临床分离株中均有体现。我们的数据表明，Pept-in 的摄取涉及 Pept-in 与细菌膜之间的静电吸引，并且遵循一种复杂的机制，可能涉及许多转运体。此外，对于那些对摄取依赖于静电吸引程度较低的 Pept-ins，细菌更难以产生耐药性，这表明未来的 Pept-ins 应该针对这一特性进行选择。
