Tharmalingam Nagendran, Jayanthan Harikrishna Sekar, Port Jenna, Rossatto Fernanda Cristina Possamai, Mylonakis Eleftherios
Houston Methodist Hospital and Houston Methodist Research Institute, Houston, Texas, USA.
Vanderblit University, Nashville, Tennessee, USA.
mBio. 2025 Apr 9;16(4):e0401624. doi: 10.1128/mbio.04016-24. Epub 2025 Feb 25.
is a high-priority organism for the development of new antibacterial treatments. We found that the antimalarial medication mefloquine (MFQ) permeabilized the bacterial cell membrane of , decreased membrane fluidity, and caused physical injury to the membrane. MFQ also maintained activity across different pH conditions (pH range: 5-8). Structure-activity relationship analysis using MFQ analogs demonstrated that piperidin-2-yl methanol is required for antibacterial activity. Scanning and transmission electron microscopy demonstrated the compromised morphological and membrane integrity in MFQ-treated cells. MFQ synergized with the membrane permeabilizers polymyxin B and colistin and the MFQ + polymyxin B combination killed bacterial cells more effectively than either treatment alone. MFQ + polymyxin B was effective against other gram-negative bacteria including , , , and . Bodipy-cadaverine displacement assays confirmed the active interaction of MFQ with other membrane lipid components, such as lipopolysaccharide, lipid A, lipoteichoic acids, and fatty acids. In all-atom molecular dynamics simulations, lipid interactions facilitated the permeation of MFQ into the simulated Gram-negative membrane. Additionally, positively charged nitrogen in the piperidine group of MFQ seems to enhance interactions with the negatively charged components of the bacterial membrane. MFQ + polymyxin B caused significantly greater curvature in the simulated membrane, indicating greater damage than standalone drug treatment. Finally, assays showed that MFQ + polymyxin B rescued larvae infected with . In conclusion, membrane-active agents such as MFQ may warrant further investigation as a potential components of gram-negative infection treatment, particularly in combination with polymyxin B.
Antimicrobial resistance is a threat globally, and new treatments are urgently needed to combat the rise of multidrug-resistant bacteria. However, the development of anti-infectives has declined over the last two decades due to regulatory, financial and long-term requirement related challenges. In this study, we examined the membrane interactions of the antiparasitic agent mefloquine (MFQ) in combination with polymyxin B, using both and approaches to evaluate their potential efficacy against gram-negative bacterial infections. We investigated the interaction of MFQ with lipid bilayers to understand the mechanism through which antibacterial activity is exerted. The piperidine moiety of MFQ plays a critical role in its interaction with the lipid bilayer and facilitates membrane permeabilization. In contrast, the membrane permeabilizer polymyxin B is associated with significant neurotoxicity and nephrotoxicity. Our findings highlight the potential of membrane-acting compounds, such as MFQ, to enhance combinatorial activity while mitigating polymyxin B-associated toxicity.
是开发新型抗菌治疗药物的高优先级研究对象。我们发现抗疟药物甲氟喹（MFQ）可使该细菌的细胞膜通透性增加，降低膜流动性，并对细胞膜造成物理损伤。MFQ在不同pH条件下（pH范围：5 - 8）均保持活性。使用MFQ类似物进行的构效关系分析表明，哌啶 - 2 - 基甲醇是抗菌活性所必需的。扫描电子显微镜和透射电子显微镜显示，经MFQ处理的细胞形态和膜完整性受损。MFQ与膜通透剂多粘菌素B和粘菌素协同作用，且MFQ + 多粘菌素B组合比单独使用任何一种药物更有效地杀死细菌细胞。MFQ + 多粘菌素B对其他革兰氏阴性菌有效，包括、、、和。Bodipy - 尸胺置换试验证实了MFQ与其他膜脂成分（如脂多糖、脂质A、脂磷壁酸和脂肪酸）之间的活性相互作用。在全原子分子动力学模拟中，脂质相互作用促进了MFQ渗透到模拟的革兰氏阴性膜中。此外，MFQ哌啶基团中的带正电荷的氮似乎增强了与细菌膜带负电荷成分的相互作用。MFQ + 多粘菌素B在模拟膜中引起的曲率明显更大，表明比单独药物处理造成的损伤更大。最后，试验表明MFQ + 多粘菌素B挽救了感染的幼虫。总之，像MFQ这样的膜活性剂作为革兰氏阴性菌感染治疗的潜在成分可能值得进一步研究，特别是与多粘菌素B联合使用时。
抗菌药物耐药性是全球面临的威胁，迫切需要新的治疗方法来应对多重耐药细菌的增加。然而，由于监管、资金和长期需求相关的挑战，抗感染药物的开发在过去二十年中有所下降。在本研究中，我们使用和方法研究了抗寄生虫药物甲氟喹（MFQ）与多粘菌素B的膜相互作用，以评估它们对革兰氏阴性菌感染的潜在疗效。我们研究了MFQ与脂质双层的相互作用，以了解其发挥抗菌活性的机制。MFQ的哌啶部分在其与脂质双层的相互作用中起关键作用，并促进膜通透性。相比之下，膜通透剂多粘菌素B具有显著的神经毒性和肾毒性。我们的研究结果突出了膜作用化合物（如MFQ）在增强联合活性同时减轻多粘菌素B相关毒性方面的潜力。
