Isolation of Dual-Active Drugs with Anticancer and Antibacterial Activities That Target Both Tubulin and FtsZ

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.