Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, 93106, USA.
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, 93106, USA; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, 95616, USA.
EBioMedicine. 2023 Mar;89:104461. doi: 10.1016/j.ebiom.2023.104461. Epub 2023 Feb 15.
Antimicrobial resistance (AMR) poses a critical threat to public health and disproportionately affects the health and well-being of persons in low-income and middle-income countries. Our aim was to identify synthetic antimicrobials termed conjugated oligoelectrolytes (COEs) that effectively treated AMR infections and whose structures could be readily modified to address current and anticipated patient needs.
Fifteen chemical variants were synthesized that contain specific alterations to the COE modular structure, and each variant was evaluated for broad-spectrum antibacterial activity and for in vitro cytotoxicity in cultured mammalian cells. Antibiotic efficacy was analyzed in murine models of sepsis; in vivo toxicity was evaluated via a blinded study of mouse clinical signs as an outcome of drug treatment.
We identified a compound, COE2-2hexyl, that displayed broad-spectrum antibacterial activity. This compound cured mice infected with clinical bacterial isolates derived from patients with refractory bacteremia and did not evoke bacterial resistance. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to negate bacterial cell viability and the evolution of drug-resistance. Disruption of these bacterial properties may occur through alteration of critical protein-protein or protein-lipid membrane interfaces-a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis.
The ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. These COE features enable the construction of a spectrum of compounds with the potential for development as a new versatile therapy for an imminent global health crisis.
U.S. Army Research Office, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute.
抗菌药物耐药性（AMR）对公共健康构成了严重威胁，并且不成比例地影响了低收入和中等收入国家人民的健康和福祉。我们的目的是确定被称为共轭寡聚电解质（COE）的合成抗菌剂，这些抗菌剂有效地治疗了 AMR 感染，并且其结构可以很容易地修改，以满足当前和预期的患者需求。
合成了十五种化学变体，这些变体包含对 COE 模块结构的特定改变，并且评估了每个变体的广谱抗菌活性和在培养的哺乳动物细胞中的体外细胞毒性。在败血症的小鼠模型中分析了抗生素疗效；通过药物治疗对小鼠临床体征进行盲法研究来评估体内毒性。
我们确定了一种化合物 COE2-2hexyl，它具有广谱抗菌活性。该化合物治愈了感染了来自耐细菌血症患者的临床分离株的小鼠，并且没有引发细菌耐药性。COE2-2hexyl 对多种与膜相关的功能（例如，分隔、运动、ATP 合成、呼吸、小分子的膜通透性）具有特异性作用，这些作用可能共同作用以消除细菌细胞活力和药物耐药性的演变。这些细菌特性的破坏可能是通过改变关键的蛋白质-蛋白质或蛋白质-脂质膜界面发生的，这是一种不同于许多破坏膜的抗菌剂或去污剂的作用机制，后者通过破坏膜来诱导细菌细胞裂解而不稳定膜。
COE 的分子设计、合成和模块化性质易于操作，与传统抗菌剂相比具有许多优势，使合成简单、可扩展且负担得起。这些 COE 特性使构建具有多种化合物的谱成为可能，这些化合物有可能开发成为一种新的、通用的治疗方法，以应对迫在眉睫的全球健康危机。
美国陆军研究办公室、美国国立过敏和传染病研究所以及美国国立心肺血液研究所。
