INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Qiang Ma,Meinuo Chen,Zhimeng Zhang,Jianuo Cen,Shiqi Chen,Qiqi Wang,Ke Han,Zhiyue Feng,Congming Wu,Chongshan Dai,Yougang Zhong,Sihan Wang,Haiyang Jiang
Methicillin-resistant Staphylococcus aureus (MRSA) represents a serious global health challenge due to its resistance to multiple antibiotics, especially β-lactams, which limits treatment options and results in high morbidity and mortality rates. Thus, there is an urgent need for effective antibacterial agents and a deeper understanding of their mechanisms of action to combat the increasingly severe threat of bacterial resistance. In this study we have performed microbiological, molecular biology experiments and molecular dynamics simulations to investigate the antimicrobial efficacy of the sanguinarine (SAN) against MRSA and its conformational modulation of the Filamentous temperature-sensitive mutant Z (FtsZ). Our findings indicate that SAN exhibits promising anti-MRSA activity and spontaneously targets the nucleoid binding domain (NBD) of SaFtsZ to inhibit bacterial division. Additionally, SAN induces multiple single-nucleotide polymorphisms (SNPs) in the SaFtsZ coding gene, including Asp187, and site-directed mutagenesis confirms the critical role of this residue in binding. Notably, SAN causes the unfolding of SaFtsZ, significantly reducing the structural flexibility required for polymerization and triggering conformational changes. At higher dimensions, SAN disrupts protofilaments assembly, ultimately inhibiting septum formation and division. These findings provide multidimensional, high-resolution insights into the interaction between SAN and SaFtsZ, offering effective strategies for the prevention and eradication of MRSA.
研究领域:
微生物学
·
药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2020
·Vol. 10
·期 25
·15000-15014
·
IF 3.119
Ying Li,Ning Sun,Hooi-Leng Ser,Wei Long,Yanan Li,Cuicui Chen,Boxin Zheng,Xuanhe Huang,Zhihua Liu,Yu-Jing Lu
New antimicrobial agents are urgently needed to address the emergence of multi-drug resistant organisms, especially those active compounds with new mechanisms of action. Based on the molecular structures of the FtsZ inhibitors reported, a variety of thiazole-quinolinium derivatives with aliphatic amino and/or styrene substituents were synthesized from benzothiazolidine derivatives. In the present study, to further explore the antibacterial potential of thiazole-quinolinium derivatives, several Gram-positive and Gram-negative bacteria were treated with the newly modified compounds and the biological effects were studied in detail in order to understand the bactericidal action of the compounds. Our findings reveal that some of these derivatives possess good potent bactericidal activity as they can inhibit Gram-positive methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and also some Gram-negative organisms and NDM-1 Escherichia coli. Furthermore, compounds 4a1–4a4 and 4b1–4b4 altered the morphology of bacterial cells and the cells displayed a more-elongated shape compared to the untreated cells. Biochemical assays showed that 4a4 and 4b4 stimulate FtsZ polymerization in bacterial cells, which eventually disrupts its dynamic assembly and Z-ring formation. The inhibition of this crucial step in bacterial cell division could potentially represent their main mechanism of antibacterial activity. Cytotoxicity assay and hemolysis assay suggested that 4a4 and 4b4 possess low cytotoxicity. In summary, these results further highlight the importance of 4a4 and 4b4 that could be developed as potent and effective bacteriostatic agents against multi-drug resistant bacteria.
研究领域:
微生物学
·
药物化学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Antibiotics-Basel
·
2025
·Vol. 14
·期 10
·1014
·
IF 4.6
Yanting Wang,Xufang Wang,Chunmeng Yao,Yaliang Zhang,Lantian Liu,Yan Cao,Bin Lu
Background: Cancer patients experience a high incidence of concomitant infections due to the effects of chemotherapy drugs and their suppressed immune function. Infection has become a major cause and an accelerating factor of cancer-related deaths. The combined use of anticancer drugs and antibiotics can produce adverse effects, necessitating the urgent search for dual-active drugs that are effective against both cancer and bacteria. Since tubulin has a homologous protein filamenting temperature-sensitive mutant Z (FtsZ) in bacteria, tubulin inhibitors have the potential to emerge as dual-active drugs against both cancer and bacteria.Methods: A comprehensive screening of a tubulin inhibitor library, encompassing 196 compounds, was conducted to evaluate their various activities.Results:Compounds6,23,33,56,60,and71exhibited both anticancer and antibacterial activities in vitro, and23,33,56,and60displayed varying degrees of FtsZ inhibitory activity. Particularly, compound23stood out as the most potent, exhibiting not only the strongest anticancer activity with IC50values of 12, 20, and 10 nM against A549, MCF-7 and Hela cells, respectively, but also the most exceptional antibacterial activity with minimum inhibitory concentration (MIC) values of 8, 8, 64, and 32 μM againstStaphylococcus aureus(S. aureus),Bacillus subtilis(B. subtilis),Escherichia coli(E. coli), andPseudomonas aeruginosa(P. aeruginosa), respectively. Furthermore, compound23possessed the superior FtsZ inhibitory activity, facilitating polymerization. This was evident in the remarkably elongated cell morphology ofBacillus subtilistreated with compound23. To gain a deeper understanding of the underlying mechanisms, molecular docking studies were conducted, revealing the interaction mode between compound23and both tubulin and FtsZ, further elucidating its multifaceted biological activities.Conclusions: The dual-active drugs obtained in this study provide a new solution to the problem of bacterial infection in cancer patients. The revealed FtsZ as the antibacterial target provides an important theoretical basis for further optimization of such drugs.
✓ 已验证
DOI
PubMed
高影响因子
PEST MANAGEMENT SCIENCE
·
2025
·
IF 3.8
Si-Yue Ma,Lin-Li Yang,Jing-Sha Yang,Ya Xiao,Guo-Qing Wang,Hong-Wu Liu,Yue Ding,Xiang Zhou,Li-Wei Liu,Zhi-Bing Wu,Song Yang
BACKGROUND FtsZ, namely filamenting temperature-sensitive mutant protein Z, is pervasive and highly conserved in the division process of prokaryotic organisms, and thus recently has come to be regarded as a key target for the development of innovative antibacterial agents. However, although its application in pesticides remains limited, initiation of a FtsZ-targeted antibacterial discovery strategy could help to prevent bacterial infection and drug/pesticide resistance. RESULTS To discover a new FtsZ inhibitor, the attractive molecular hybridization strategy of introducing isopropanolamine linker was used in which representative active scaffolds for FtsZ inhibitors including coumarin and cinnamic acids were selected to devise new coumarin–cinnamic acid hybrids. Interestingly, compound 4d exhibited excellent in vitro antibacterial activity toward Xanthomonas oryzae pv. oryzae [ Xoo , median effective concentration (EC 50 ) = 1.45 mg L −1 ], which was better than that of the reference reagent bismerthiazol (EC 50 = 33.08 mg L −1 ), and demonstrated commendable in vivo anti- Xoo activity (protective activity: 50.46% for 200 mg L −1 ). Furthermore, mechanistic assays including fluorescence imaging, guanosine triphosphatase (GTPase) activity assay, fluorometric titration assays, Fourier transform infrared spectroscopy and computational simulations co-elucidated that compound 4d may selectively act on the guanosine 5′-triphosphate (GTP) binding site, further suppress the GTPase activity [median inhibitory concentration(IC 50 )value of compound 4d of 170.55 μ m ), thereby inhibiting bacterial reproduction. Toxicity studies accentuated the favorable pharmacological profile and low plant toxicity of compound 4d . CONCLUSION This study provides a new paradigm for extending new bactericides to efficiently control bacterial infections by targeting FtsZ. The work provides new insights for addressing bacterial drug resistance and overcoming bottlenecks in the development of novel pesticides. © 2025 Society of Chemical Industry.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2025
·
IF 4.5
Wenlong Chen,Shuixian Zhang,Chunxu Huang,Zhiming Hu,Ting Cao,Jun Mou,Xinxia Gu,Meiling Sun,Jie Liu
The escalating threat of methicillin-resistant Staphylococcus aureus (MRSA) necessitates novel therapeutic strategies. Our previous work suggested that an extract from Cyclocarya paliurus leaves (ECPL) inhibits MRSA by targeting the cell division protein FtsZ. Here, guided by anti-MRSA activity, we isolated three compounds from ECPL: asiatic acid (AA), maslinic acid (MA), and ursolic acid (UA). They exhibited antibacterial activity against MRSA and induced cell elongation, indicative of division arrest. Time-kill assays showed AA and MA are bactericides, while UA is bacteriostatic. Mechanistically, these compounds disrupt cell division by differentially affecting FtsZ dynamics: AA promotes polymerization, whereas MA and UA inhibit it. SPR analysis showed direct FtsZ binding to AA (Kd = 2.4 μM), MA (Kd = 9.8 μM), and UA (Kd = 0.7 μM). Molecular docking predicted a shared FtsZ binding pocket but revealed that AA adopts a distinct conformation driven by unique interactions, including a hydrogen bond with Arg191—an interaction not observed for MA or UA, which instead form hydrogen bonds with Thr265 and Thr309. Despite these divergent effects on polymerization and distinct binding modes, all compounds ultimately disrupted Z-ring assembly and septum formation. In a murine skin infection model, AA, selected for its bactericidal activity and unique FtsZ modulation mechanism, significantly reduced bacterial burden and accelerated wound healing. Collectively, our findings validate these compounds as direct FtsZ-targeting agents and establish AA as a promising anti-MRSA lead compound with a novel mechanism disrupting the bacterial divisome.
✓ 已验证
DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2021
·
IF 5.645
Xiang Zhou,Haojie Ye,Xiuhui Gao,Yumei Feng,Wubin Shao,Puying Qi,Zhibing Wu,Liwei Liu,Peiyi Wang,Song Yang
Natural products (NPs) are inexhaustible wellsprings for new agrochemicals discovery. To excavate novel natural products-based antibacterial leads or candidates potentially targeting FtsZ (filamentous temperature-sensitive protein Z) which is widely regarded as a promising antibacterial target for novel drug discovery, herein, a rapid and efficient screening platform was initially established to disclose the potential FtsZ inhibitors from a variety of commercial natural products. Screening results revealed that 4'-demethylepipodophyllotoxin (DMEP) from renewable Dysosma versipellis ( D. versipellis ) species could distinctly decrease the Xoo FtsZ’ GTPase activity and afforded a ponderable bacteriostatic effect (EC 50 = 38.7 mg L -1 ) against Xanthomonas oryzae pv. oryzae ( Xoo ). Further explorations found that DMEP could disorganize the assembly dynamics of Xoo FtsZ, and thereby yielding long and filamentous Xoo cells from the transmission electron microscopic and fluorescence microscopic imaging. Molecular docking study showed that DMEP displayed strong interactions with Asp38 and Arg205 residues of Xoo FtsZ, indicating that a natural potential FtsZ inhibitor was discovered gradually. The following bioassay result against rice bacterial blight in vivo presented good curative activity (50.0% at 200 mg L −1 ) and protective activity (46.8% at 200 mg L −1 ). Given that natural DMEP has many sites for structural modification, therefore, it can concurrently serve as a novel lead compound for exploring highly bioactive FtsZ inhibitors based on the molecular skeleton of DMEP.
研究领域:
植物学
·
微生物学
·
农业科学
✓ 已验证
产品关联
DOI
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2022
·
IF 6.449
Meiling Sun,Zhenghui Luo,Qi Yang,Chunxu Huang,Yu Kuang,Mei Kang,Jie Liu
Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to tolerate almost all known β-lactam antibiotics, and been exhibiting resistance to vancomycin . Developing new drugs against the MRSA infection are urgently needed. Natural resource is enriched with antimicrobial molecules. Here, we report an extract from leaves of Cyclocarya paliurus (ECPL), a species of tree native to China and being traditionally cultivated as medicinal plant , which shows a broad spectrum of bacteriostatic and bactericidal effects at MIC 50 15.99 ± 0.55 μg/ml against methicillin-susceptible and -resistant S. aureus . The ECPL suppresses bacterial expression of FtsZ at both transcriptional and protein levels, inhibits its GTPase activity, blocks the assembly dynamics of FtsZ, and disrupts the formation of Z-ring. The bacteria cells fail to divide, enlarge initially, and lyse eventually. In mouse model, the ECPL facilitates skin wound healing with MRSA infection as effective as vancomycin. Our study unveils the potential of identifying novel molecule in ECPL for development of new class of antibiotic against both methicillin-susceptible and -resistant S. aureus , and support domestication of the C. paliurus growing from wild to cultivated, and further scale up the cultivation into industrialized farm for sustainable harvest for pharmaceutic interest.
研究领域:
微生物学
·
药理学
·
植物科学
·
传染病学
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Liu Zhi-Hai,Wang Wei-Mei,Zhang Zhen,Sun Liang,Wu Shuai-Cheng
The emergence and spread of antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), underly the urgent need to develop novel antibacterial drugs. Macleaya cordata, a traditional medicinal plant, has been widely used in livestock animals, plants, and humans. Alkaloids are the primary bioactive compounds of Macleaya cordata and exhibit antibacterial, antiinflammatory, and antioxidant activities. Nevertheless, the antibacterial compounds and mode of action of Macleaya cordata remain unclear. In the present study, we investigated the antibacterial activity and mode of action of alkaloids from Macleaya cordata. Sanguinarine, 6-ethoxysanguinarine (6-ES), 6-methoxydihydrosanguinarine (6-MS), chelerythrine (CH), and dihydrochelerythrine (DICH) exhibited good antibacterial activity against Gram-positive bacteria, including MRSA. 6-ES rapidly killed MRSA, possibly by interfering with membrane and metabolic functions including ROS production by targeting the membrane and FtsZ in S. aureus. Additionally, 6-ES directly suppressed the hemolytic activity of α-hemolysin, alleviated inflammatory responses, and eliminated intracellular MRSA, as well as displayed low development of drug resistance, in vitro. Finally, a 6-ES-loaded thermosensitive hydrogel promoted wound healing in mice infected with MRSA. These results supported 6-ES as a novel potential candidate or leading compound with antibacterial, antivirulence, and host immunomodulatory activities in fighting against bacterial infections.
研究领域:
药理学
·
微生物学
·
传染病学
·
植物科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2020
·
IF 4.192
Xiang Zhou,Yu-Mei Feng,Pu-Ying Qi,Wu-Bin Shao,Zhi-Bing Wu,Li-Wei Liu,Yi Wang,Hao-Dong Ma,Pei-Yi Wang,Zhong Li,Song Yang
Xanthomonas oryzae pv. oryzae (Xoo) is an offensive phytopathogen that can invade a wide range of plant hosts to develop bacterial diseases, including the well-known rice bacterial leaf blight. However, few agrochemicals have been identified to effectively prevent and eliminate Xoo-induced diseases. Thus, designing novel antibacterial compounds on the basis of the potential targets from Xoo may lead to the discovery of highly efficient and innovative anti-Xoo agents. Filamentous temperature-sensitive protein Z (FtsZ), an important functional protein in the progression of cell division, has been widely reported and exploited as a target for creating antibacterial drugs in the field of medicine. Therefore, the fabrication of innovative frameworks targeting XooFtsZ may be an effective method for managing bacterial leaf blight diseases via blocking the binary division and reproduction of Xoo. As such, a series of novel N-(cinnamoyl)-N′-(substituted)acryloyl hydrazide derivatives containing pyridinium moieties were designed, and the anti-Xoo activity was determined. The bioassay results showed that compound A7 had excellent anti-Xoo activity (EC50 = 0.99 mg L–1) in vitro and distinct curative activity (63.2% at 200 mg L–1) in vivo. Further studies revealed that these designed compounds were XooFtsZ inhibitors, validating by the reduced GTPase activity of recombinant XooFtsZ, the nonfilamentous XooFtsZ assembly observed in the TEM images, and the prolonged Xoo cells from the fluorescence patterns. Computational docking studies showed that compound A7 had strong interactions with ASN34, GLN193, and GLN197 residues located in the α helix regions of XooFtsZ. The present study demonstrates the developed FtsZ inhibitors can serve as agents to control Xoo-induced infections.
研究领域:
植物病理学
·
分子生物学
·
药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）