Ramirez Danzel Marie, Ramirez Danyel, Dhiman Shiv, Arora Rajat, Lozeau Christian, Arthur Gilbert, Zhanel George, Schweizer Frank
Department of Chemistry, University of Manitoba, Winnipeg, MBR3T 2N2, Canada.
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MBR3E 0W2, Canada.
ACS Infect Dis. 2023 Sep 8;9(9):1754-1768. doi: 10.1021/acsinfecdis.3c00217. Epub 2023 Aug 21.
Carbapenem-resistant () was designated as a critical priority pathogen by the World Health Organization for which new therapeutic solutions are required. With the rapid dissemination of β-lactamases in , β-lactam (BL) antibiotics are used in conjunction with β-lactamase inhibitors (BLI). The effectiveness of the BL/BLI combination could be further enhanced with the inclusion of an outer membrane (OM) permeabilizer, such as aminoglycosides and aminoglycoside-based adjuvants. Thus, the development of seven tobramycin derivatives reported herein focused on improving OM permeabilizing capabilities and reducing associated toxicity. The structure-activity relationship studies emphasized the effects of the nature of the cationic group; the number of polar head groups and positive charges; and flexibility, length, and steric bulk of the hydrophobic moiety. The optimized guanidinylated tobramycin-biphenyl derivative was noncytotoxic and demonstrated the ability to potentiate ceftazidime and aztreonam monotherapy and in dual combinations with avibactam against multidrug-resistant (MDR) and β-lactamase harboring isolates of . The triple combination of ceftazidime/avibactam plus guanidinylated tobramycin-biphenyl resulted in rapid bactericidal activity within 4-8 h of treatment, demonstrating the potential application of these guanidinylated amphiphilic tobramycin derivatives in augmenting BL/BLI combinations.
耐碳青霉烯类肠杆菌科细菌（CRE）被世界卫生组织指定为急需新治疗方案的关键优先病原体。随着β-内酰胺酶在CRE中迅速传播，β-内酰胺（BL）抗生素与β-内酰胺酶抑制剂（BLI）联合使用。加入外膜（OM）通透剂，如氨基糖苷类和基于氨基糖苷类的佐剂，可进一步增强BL/BLI组合的有效性。因此，本文报道的七种妥布霉素衍生物的研发重点是提高OM通透能力并降低相关毒性。构效关系研究强调了阳离子基团性质、极性头基团数量和正电荷数量，以及疏水部分的柔韧性、长度和空间体积的影响。优化后的胍基化妥布霉素-联苯衍生物无细胞毒性，并证明能够增强头孢他啶和氨曲南单药治疗以及与阿维巴坦联合使用时对多重耐药（MDR）和携带β-内酰胺酶的CRE分离株的疗效。头孢他啶/阿维巴坦加胍基化妥布霉素-联苯的三联组合在治疗4-8小时内产生快速杀菌活性，证明了这些胍基化两亲性妥布霉素衍生物在增强BL/BLI组合方面的潜在应用。
