School of Dentistry, Cardiff University, Cardiff, United Kingdom.
Destiny Pharma plc, Brighton, United Kingdom.
Front Cell Infect Microbiol. 2022 Jun 30;12:904465. doi: 10.3389/fcimb.2022.904465. eCollection 2022.
With increasing incidence of antimicrobial resistance, there is an urgent need for novel and effective antibacterials. Destiny Pharma plc have developed a series of porphyrin-based XF drugs, some with dual mechanisms of antibacterial action. An innate mechanism acts through binding to the outer bacterial membrane and a separate, light-activated, photodynamic (PD) mechanism, acts the generation of reactive oxygen species. This study aimed to assess the innate and PD associated antibacterial activity of XF drugs against planktonic bacteria, their biofilms and combinational effects with conventional antibiotics. Minimum inhibitory concentrations (MICs) were determined for 3 XF drugs against 114 bacterial isolates. MICs for XF-73 and XF-70 were determined (± PD). DPD-207 was designed to not exhibit PD action due to its structure. XF-drugs (± PD) were further assessed for synergy with conventional antibiotics (using a checkerboard assay) and antibiofilm activity against susceptible strains. XF drugs were innately active against all tested Gram-positive isolates. PD action significantly increased bacterial susceptibility to XF-73 and XF-70 for all Gram-positive isolates. Generally, the XF drugs exhibited higher MICs against Gram-negative isolates, however PD significantly enhanced potency, particularly for XF-70. XF-73 and XF-70 exhibited synergy with ertapenem against a methicillin resistant (MRSA) strain (± PD) and XF-73 with polymyxin B (± PD) against . No antagonism was seen between the XF drugs and any of the 5 antibiotics tested. The antibiofilm effect of XF drugs was also observed for all isolates tested. Generally, PD did not enhance activity for other bacterial isolates tested with the exception of XF-73 against biofilms. XF drugs exhibited significant antimicrobial activity against Gram-positive bacteria, with PD enhancement of bacterial susceptibility. Additionally, XF drugs displayed synergy with conventional antibiotics and demonstrated antibiofilm effects.
随着抗菌药物耐药性的不断增加，我们迫切需要新型、有效的抗菌药物。Destiny Pharma plc 开发了一系列基于卟啉的 XF 药物，其中一些具有双重抗菌作用机制。一种固有机制通过与外膜结合发挥作用，另一种独立的、光激活的光动力（PD）机制通过产生活性氧物质发挥作用。本研究旨在评估 XF 药物对浮游菌、生物膜的固有和 PD 相关抗菌活性，以及与传统抗生素的联合作用。测定了 3 种 XF 药物对 114 种细菌分离株的最低抑菌浓度（MIC）。测定了 XF-73 和 XF-70 的 MIC（±PD）。由于其结构，DPD-207 被设计为不表现出 PD 作用。进一步评估了 XF-药物（±PD）与传统抗生素（棋盘试验）的协同作用以及对敏感菌株的抗生物膜活性。XF 药物对所有测试的革兰氏阳性分离株均具有固有活性。PD 作用显著提高了所有革兰氏阳性分离株对 XF-73 和 XF-70 的细菌敏感性。一般来说，XF 药物对革兰氏阴性分离株的 MIC 较高，但 PD 显著提高了效力，尤其是 XF-70。XF-73 和 XF-70 与厄他培南（±PD）对耐甲氧西林金黄色葡萄球菌（MRSA）菌株表现出协同作用，与多粘菌素 B（±PD）对 表现出协同作用。XF 药物与 5 种测试抗生素之间未观察到拮抗作用。XF 药物对所有测试的分离株也表现出抗生物膜作用。一般来说，PD 没有增强除 XF-73 对 生物膜以外的其他细菌分离株的活性。XF 药物对革兰氏阳性菌表现出显著的抗菌活性，PD 增强了细菌的敏感性。此外，XF 药物与传统抗生素显示出协同作用，并表现出抗生物膜作用。
