Ul Hassan Syed Shams, Ahmad Naveed, Rehman Abdur, Pan Chengqian, Wu Jiajia, Li Tao, Yan Shi-Kai, Jin Huizi
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Joint Center for Single Cell Biology, Shanghai Collaborative Innovation Center of Agri-Seeds, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China.
Eur J Med Chem. 2025 Nov 5;297:117967. doi: 10.1016/j.ejmech.2025.117967. Epub 2025 Jul 18.
The rapid rise of antibiotic resistance among bacterial pathogens threatens global health, rendering many existing drugs ineffective and creating an urgent demand for new therapeutic strategies. To the best of our knowledge, this is the first work reporting the detailed antibacterial mechanism of action of twelve targeted genes. Here, we evaluated the marine-derived compound CDPDP for its antibacterial activity against Staphylococcus aureus (S.A.) and Riemerella anatipestifer (R.A.), demonstrating potent bactericidal effects (IC = 300 μM for S.A.; 100 μM for R.A.). Scanning electron microscopy revealed pronounced morphological alterations in treated cells, including cell shrinkage, membrane blebbing, and wall irregularities. Comparative transcriptome analysis uncovered that CDPDP exerts its antibacterial activity in S.A. primarily through targeting DNA/nucleic acid-binding genes-downregulating key replication and repair factors (SSB, DnaN, RecF, MutS, PolA, LigA)-while in R.A. it disrupts membrane integrity by suppressing genes involved in outer-membrane biogenesis and protein translocation (SecY, SecG, TatA, YajC, MurC, AccB). Validation via qRT-PCR consistently confirmed the RNA-Seq differential expression patterns, verifying the downregulation of DNA-binding and membrane-associated genes in both pathogens after CDPDP treatment, and molecular docking identified crucial amino acid interactions mediating CDPDP binding (Arg1086/Thr1098 in SSB; Phe78/Ile82 in SecY). Molecular dynamics simulations further substantiated the stability of these interactions under physiological conditions. Additionally, in silico epoxidation and N-dealkylation predictions reveal potential metabolic transformations that could influence CDPDP's bioactivity. Collectively, these findings unveil a dual antibacterial mechanism-DNA-targeted lethality in Gram-positives and membrane disruption in Gram-negatives-demonstrating CDPDP's potential as a broad-spectrum, resistance-resilient antibiotic lead.
细菌病原体中抗生素耐药性的迅速上升威胁着全球健康，使许多现有药物失效，并催生了对新治疗策略的迫切需求。据我们所知，这是第一项详细报道12个靶向基因抗菌作用机制的研究。在此，我们评估了海洋来源化合物CDPDP对金黄色葡萄球菌（S.A.）和鸭疫里默氏菌（R.A.）的抗菌活性，结果显示其具有强大的杀菌作用（对S.A.的IC = 300 μM；对R.A.的IC = 100 μM）。扫描电子显微镜显示处理后的细胞出现明显的形态改变，包括细胞收缩、膜泡化和细胞壁不规则。比较转录组分析发现，CDPDP在S.A.中发挥抗菌活性主要是通过靶向DNA/核酸结合基因——下调关键的复制和修复因子（SSB、DnaN、RecF、MutS、PolA、LigA），而在R.A.中，它通过抑制参与外膜生物合成和蛋白质转运的基因（SecY、SecG、TatA、YajC、MurC、AccB）来破坏膜的完整性。通过qRT-PCR进行的验证始终证实了RNA测序的差异表达模式，验证了CDPDP处理后两种病原体中DNA结合基因和膜相关基因的下调，分子对接确定了介导CDPDP结合的关键氨基酸相互作用（SSB中的Arg1086/Thr1098；SecY中的Phe78/Ile82）。分子动力学模拟进一步证实了这些相互作用在生理条件下的稳定性。此外，计算机模拟的环氧化和N-脱烷基化预测揭示了可能影响CDPDP生物活性的潜在代谢转化。总的来说，这些发现揭示了一种双重抗菌机制——革兰氏阳性菌中的DNA靶向致死性和革兰氏阴性菌中的膜破坏，证明了CDPDP作为一种广谱且抗耐药性的抗生素先导物的潜力。
