Function-oriented synthesis of marine phidianidine derivatives as potent anti-MRSA agents

Abstract

The rapid emergence of multidrug-resistant bacterial pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), underscores the critical discovery for new antibiotics with novel scaffolds. We identified lead compound LXW933, which exhibits promising anti-MRSA activity and features a unique 1,2,4-oxadiazole scaffold, from our phidianidine-based compound library. Based on this structure, a Function-Oriented Synthesis (FOS) strategy had been conducted to afford a series of phidianidine derivatives for their antibacterial activity evaluation. Compounds 24a exhibited excellent anti-MRSA efficacy with an MIC value of 1.5 μg/mL and low toxicity against HeLa cells. Further mechanistic study showed that 24a effectively inhibits biofilm formation and exerts its antibacterial effect by disrupting the bacterial cell membrane. This research provides valuable insights for the discovery of antibacterial drug leads derived from oxadiazole-containing marine alkaloids, paving the way for new strategies to combat antimicrobial resistance.

Keywords

Marine natural products / Phidianidines / Antibacterial activity / Structure-activity relationship

Funding

This work was supported by the Key R&D Program of Shandong Province (Nos. 2024CXPT028 and 2025CXPT012), the National Key Research and Development Program of China (No. 2021YFF0502400), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB1060000), and Taishan Scholars Program (tsqn2023-12302), the Natural Science Foundation of China (Nos. 42576087), 2025 Annual Self-deployment Project of State Key Laboratory of Chemical Biology (No. SKLCB-2025-06), the Fundamental Research Projects of Science & Technology Innovation and Development Plan in Yantai City(No. 2023JCYJ057).

Declaration of competing interest

These authors have no conflict of interest to declare.

Supporting Information

Supporting information can be requested by sending E-mail to the corresponding authors.

References

[1] Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022; 399(10325):629-655. https://doi.org/10.1016/S0140-6736(21)02724-.

[2] Chen QQ, Ding YH, Li ZY, et al. Comprehensive analysis of the antibacterial activity of 5,8-dihydroxy-1,4-naphthoquinone derivatives against methicillin-resistant Staphylococcus aureus. Chin J Nat Med. 2025; 23(5):604-613. https://doi.org/10.1016/S1875-5364(25)60818-.

[3] Smith WPJ, Wucher BR, Nadell CD, et al. Bacterial defences: mechanisms, evolution and antimicrobial resistance. Nat Rev Microbiol. 2023; 21(8):519-534. https://doi.org/10.1038/s41579-023-00877-3.

[4] Ampomah-Wireko M, Qu Y, Li D, et al. Design, synthesis and antibacterial evaluation of oxazolidinone derivatives containing N-methylglycyl or quaternary ammonium salts. Bioorg Med Chem. 2025; 122:118144. https://doi.org/10.1016/j.bmc.2025.118144.

[5] Kong QD, Yang YS.Recent advances in antibacterial agents. Bioorg Med Chem Lett. 2021; 35:127799. https://doi.org/10.1016/j.bmcl.2021.127799.

[6] Kokot M, Anderluh M, Hrast M, et al. The structural features of novel bacterial topoisomerase inhibitors that define their activity on topoisomerase IV. J Med Chem. 2022; 65(9):6431-6440. https://doi.org/10.1021/acs.jmedchem.2c00039.

[7] Wu J, Song T, Zhang L, et al. Antibacterial and cytotoxic metabolites produced by Streptomyces tanashiensis BYF-112 isolated from Odontotermes formosanus. Chin J Nat Med. 2024; 22(9):822-830. https://doi.org/10.1016/s1875-5364(24)60720-.

[8] Zhao SF, Jing ZW. New pimarane diterpenoids with antibacterial activity from fungus Arthrinium sp. ZS03. Chin J Nat Med. 2024; 22(4):356-364. https://doi.org/10.1016/S1875-5364(24)60629-.

[9] Huang C, Jing Y, Fu PP, et al. Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening. Acta Pharm Sin B. 2024; 14(11):4914-4933. https://doi.org/10.1016/j.apsb.2024.07.019.

[10] Xu Q, Du YQ, Chen PP, et al. Computation assisted chemical study of photo-induced late-stage skeleton transformation of marine natural products towards new scaffolds with biological functions. Chin Chem Lett. 2025; 36(5):110141. https://doi.org/10.1016/j.cclet.2024.110141.

[11] Gao CL, Song JQ, Yang ZN, et al. Chemoproteomics of marine natural product naamidine J unveils CSE1L as a therapeutic target in acute lung injury. J Am Chem Soc. 2024; 146(41):28384-28397. https://doi.org/10.1021/jacs.4c09695.

[12] Cui YY, Jin Y, Sun RN, et al. The first discovery of marine polyoxygenated cembranolides as potential agents for the treatment of ulcerative colitis. J Med Chem. 2024; 67(14):12248-12260. https://doi.org/10.1021/acs.jmedchem.4c00950.

[13] Zhang XY, Su MZ, Zhu MX, et al. The biologically and ecologically important natural products from the Chinese sea hare Bursatella leachii: structures, stereochemistry and beyond. Chin J Nat Med. 2024; 22(11):1030-1039. https://doi.org/10.1016/s1875-5364(24)60611-.

[14] Xu Q, Yan BY, Wang HF, et al. Total synthesis of nocarterphenyl A, 2-dehydroxymethylnocarterphenyl A and nocarterphenyl D produced by marine Nocardiopsis spp. J Nat Prod. 2025; 88(11):2710-2718. https://doi.org/10.1021/acs.jnatprod.5c01038.

[15] Tao XY, Wang HR, Wang Q, et al. Marine natural product chagosendine C induces cuproptosis in colorectal cancer cells by targeting FDX1. J Am Chem Soc. 2025; 147(41):37089-37103. https://doi.org/10.1021/jacs.5c07917.

[16] Carbone M, Li Y, Irace C, et al. Structure and cytotoxicity of phidianidines A and B: first finding of 1,2,4-oxadiazole system in a marine natural product. Org Lett. 2011; 13(10):2516-2519. https://doi.org/10.1021/ol200234.

[17] Jiang CS, Fu Y, Zhang L, et al. Synthesis and biological evaluation of novel marine-derived indole-based 1,2,4-oxadiazoles derivatives as multifunctional neuroprotective agents. Bioorg Med Chem Lett. 2015; 25(2):216-220. https://doi.org/10.1016/j.bmcl.2014.11.068.

[18] Zhang L, Jiang CS, Gao LX, et al. Design, synthesis and in vitro activity of phidianidine B derivatives as novel PTP1B inhibitors with specific selectivity. Bioorg Med Chem Lett. 2016; 26(3):778-781. https://doi.org/10.1016/j.bmcl.2015.12.097.

[19] Labriere C, Elumalai V, Staffansson J, et al. Phidianidine A and synthetic analogues as naturally inspired marine antifoulants. J Nat Prod. 2020; 83(11):3413-3423. https://doi.org/10.1021/acs.jnatprod.0c00881.

[20] Brogan JT, Stoops SL, Lindsley CW. Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets. ACS Chem Neurosci. 2012; 3(9):658-664. https://doi.org/10.1021/cn300064.

[21] Xie HX, Wang YH, Zhang JH, et al. Design, synthesis and biological evaluation of marine phidianidine-inspired derivatives against oxidized ldl-induced endothelial injury by activating Nrf 2 anti-oxidation pathway. Bioorg Chem. 2022; 120:105606. https://doi.org/10.1016/j.bioorg.2022.105606.

[22] Xu Q, Zhao N, Liu J, et al. Design, synthesis and in vitro biological evaluation of marine phidianidine derivatives as potential anti-inflammatory agents. Bioorg Med Chem. 2022; 71:116936. https://doi.org/10.1016/j.bmc.2022.116936.

[23] Liu J, Li H, Chen KX, et al. Design and synthesis of marine phidianidine derivatives as potential immunosuppressive agents. J Med Chem. 2018; 61(24):11298-11308. https://doi.org/10.1021/acs.jmedchem.8b01430.

[24] O'Daniel PI, Peng Z, Pi H, et al. Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with Gram-positive antibacterial activity. J Am Chem Soc. 2014; 136(9):3664-3672. https://doi.org/10.1021/ja500053.

[25] Barbachyn MR. Identification of a 1,2,4-oxadiazole with potent and specific activity against Clostridioides difficile, the causative bacterium of C. difficile infection, an urgent public health threat. J Med Chem. 2023; 66(20):13888-13890. https://doi.org/10.1021/acs.jmedchem.3c01778.

[26] Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Approved Standard, 9^ed edition (document M7-A7), 2018, Wayne, PA, USA.

[27] Jia J, Zheng MX, Zhang CW, et al. Killing of Staphylococcus aureus persisters by a multitarget natural product chrysomycin A. Sci Adv. 2023; 9(31):5995. https://doi.org/10.1126/sciadv.adg5995.

[28] Chang TP, Chen ZF, Sheng LS, et al. Unanticipated quinoline modification on vancomycin as an effective atrategy to alter the antibacterial profile and combat multidrug resistance. J Am Chem Soc. 2025; 147(46):42670-42684. https://doi.org/10.1021/jacs.5c14268.s001.