Pirhaghi Mitra, Najarzadeh Zahra, Moosavi-Movahedi Faezeh, Shafizadeh Mahshid, Mamashli Fatemeh, Atarod Deyhim, Ghasemi Atiyeh, Morshedi Dina, Meratan Ali Akbar, Otzen Daniel E, Saboury Ali Akbar
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, 8000 Aarhus C, Denmark.
Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, 8000 Aarhus C, Denmark.
Biochim Biophys Acta Proteins Proteom. 2023 Feb 1;1871(2):140883. doi: 10.1016/j.bbapap.2022.140883. Epub 2022 Nov 29.
Multidrug resistance of bacteria and persistent infections related to biofilms, as well as the low availability of new antibacterial drugs, make it urgent to develop new antibiotics. Here, we evaluate the antibacterial and anti-biofilm properties of ticlopidine (TP), an anti-platelet aggregation drug, TP showed antibacterial activity against both gram-positive (MRSA) and gram-negative (E. coli, and P. aeruginosa) bacteria over a long treatment period. TP significantly reduced the survival of gram-negative bacteria in human blood though impact on gram-positives was more limited. TP may cause death in MRSA by inhibiting staphyloxanthin pigment synthesis, leading to oxidative stress, while scanning electron microscopy imaging indicate a loss of membrane integrity, damage, and consequent death due to lysis in gram-negative bacteria. TP showed good anti-biofilm activity against P. aeruginosa and MRSA, and a stronger biofilm degradation activity on P. aeruginosa compared to MRSA. Measuring fluorescence of the amyloid-reporter Thioflavin T (ThT) in biofilm implicated inhibition of amyloid formation as part of TP activity. This was confirmed by assays on the purified protein in P. aeruginosa, FapC, whose fibrillation kinetics was inhibited by TP. TP prolonged the lag phase of aggregation and reduced the subsequent growth rate and prolonging the lag phase to very long times provides ample opportunity to exert TP's antibacterial effect. We conclude that TP shows activity as an antibiotic against both gram-positive and gram-negative bacteria thanks to a broad range of activities, targeting bacterial metabolic processes, cellular structures and the biofilm matrix.
细菌的多重耐药性以及与生物膜相关的持续性感染，再加上新型抗菌药物的可获得性低，使得开发新抗生素变得迫在眉睫。在此，我们评估了抗血小板聚集药物噻氯匹定（TP）的抗菌和抗生物膜特性，TP在较长治疗期内对革兰氏阳性菌（耐甲氧西林金黄色葡萄球菌，MRSA）和革兰氏阴性菌（大肠杆菌和铜绿假单胞菌）均显示出抗菌活性。TP虽对革兰氏阳性菌的影响较为有限，但能显著降低革兰氏阴性菌在人血液中的存活率。TP可能通过抑制金黄色葡萄球菌黄素色素合成导致氧化应激，从而致使MRSA死亡，而扫描电子显微镜成像显示革兰氏阴性菌因膜完整性丧失、受损并最终因裂解而死亡。TP对铜绿假单胞菌和MRSA表现出良好的抗生物膜活性，且对铜绿假单胞菌的生物膜降解活性比对MRSA更强。检测生物膜中淀粉样蛋白报告分子硫黄素T（ThT）的荧光表明，抑制淀粉样蛋白形成是TP活性的一部分。这在对铜绿假单胞菌纯化蛋白FapC的检测中得到证实，其纤维状动力学受到TP抑制。TP延长了聚集的延迟期并降低了随后的生长速率，将延迟期延长至很长时间为发挥TP的抗菌作用提供了充足机会。我们得出结论，由于TP具有广泛的活性，靶向细菌代谢过程、细胞结构和生物膜基质，它作为一种抗生素对革兰氏阳性菌和革兰氏阴性菌均具有活性。
