Chmielewska Sylwia Joanna, Skłodowski Karol, Depciuch Joanna, Deptuła Piotr, Piktel Ewelina, Fiedoruk Krzysztof, Kot Patrycja, Paprocka Paulina, Fortunka Kamila, Wollny Tomasz, Wolak Przemysław, Parlinska-Wojtan Magdalena, Savage Paul B, Bucki Robert
Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, 15-222 Bialystok, Poland.
Institute of Nuclear Physics, Polish Academy of Sciences, 31-342 Krakow, Poland.
Pharmaceutics. 2021 Mar 22;13(3):425. doi: 10.3390/pharmaceutics13030425.
The ever-growing number of infections caused by multidrug-resistant (MDR) bacterial strains requires an increased effort to develop new antibiotics. Herein, we demonstrate that a new class of gold nanoparticles (Au NPs), defined by shape and conjugated with ceragenin CSA-131 (cationic steroid antimicrobial), display strong bactericidal activity against intractable superbugs.
For the purpose of research, we developed nanosystems with rod- (AuR NPs@CSA-131), peanut-(AuP NPs@CSA-131) and star-shaped (AuS NPs@CSA-131) metal cores. Those nanosystems were evaluated against bacterial strains representing various groups of MDR (multidrug-resistant) Gram-positive (MRSA, MRSE, and MLS) and Gram-negative (ESBL, AmpC, and CR) pathogens. Assessment of MICs (minimum inhibitory concentrations)/MBCs (minimum bactericidal concentrations) and killing assays were performed as a measure of their antibacterial activity. In addition to a comprehensive analysis of bacterial responses involving the generation of ROS (reactive oxygen species), plasma membrane permeabilization and depolarization, as well as the release of protein content, were performed to investigate the molecular mechanisms of action of the nanosystems. Finally, their hemocompatibility was assessed by a hemolysis assay.
All of the tested nanosystems exerted potent bactericidal activity in a manner resulting in the generation of ROS, followed by damage of the bacterial membranes and the leakage of intracellular content. Notably, the killing action occurred with all of the bacterial strains evaluated, including those known to be drug resistant, and at concentrations that did not impact the growth of host cells.
Conjugation of CSA-131 with Au NPs by covalent bond between the COOH group from MHDA and NH from CSA-131 potentiates the antimicrobial activity of this ceragenin if compared to its action alone. Results validate the development of AuR NPs@CSA-131, AuP NPs@CSA-131, and AuS NPs@CSA-131 as potential novel nanoantibiotics that might effectively eradicate MDR bacteria.
耐多药（MDR）细菌菌株引起的感染数量不断增加，这就需要加大力度研发新型抗生素。在此，我们证明了一类新型金纳米颗粒（Au NPs），其由形状定义并与杀菌肽CSA-131（阳离子类固醇抗菌剂）偶联，对难治性超级细菌具有强大的杀菌活性。
为了进行研究，我们开发了具有棒状（AuR NPs@CSA-131）、花生状（AuP NPs@CSA-131）和星形（AuS NPs@CSA-131）金属核的纳米系统。针对代表各种耐多药（MDR）革兰氏阳性（MRSA、MRSE和MLS）和革兰氏阴性（ESBL、AmpC和CR）病原体组的细菌菌株对这些纳米系统进行了评估。进行最低抑菌浓度（MICs）/最低杀菌浓度（MBCs）评估和杀菌试验，以衡量它们的抗菌活性。除了对涉及活性氧（ROS）生成、质膜通透性和去极化以及蛋白质含量释放的细菌反应进行全面分析外，还进行了研究以探究纳米系统的分子作用机制。最后，通过溶血试验评估它们的血液相容性。
所有测试的纳米系统均以产生ROS的方式发挥强大的杀菌活性，随后细菌膜受损且细胞内物质泄漏。值得注意的是，对所有评估的细菌菌株均产生了杀菌作用，包括那些已知具有耐药性的菌株，且浓度不会影响宿主细胞的生长。
与单独作用相比，通过MHDA的COOH基团与CSA-131的NH之间的共价键将CSA-131与Au NPs偶联可增强这种杀菌肽的抗菌活性。结果验证了AuR NPs@CSA-131、AuP NPs@CSA-131和AuS NPs@CSA-131作为可能有效根除耐多药细菌的潜在新型纳米抗生素的开发。
