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

<b>Background</b>: 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. <b>Methods</b>: A comprehensive screening of a tubulin inhibitor library, encompassing 196 compounds, was conducted to evaluate their various activities. <b>Results:</b> Compounds <b>6</b>, <b>23</b>, <b>33</b>, <b>56</b>, <b>60,</b> and <b>71</b> exhibited both anticancer and antibacterial activities in vitro, and <b>23</b>, <b>33</b>, <b>56,</b> and <b>60</b> displayed varying degrees of FtsZ inhibitory activity. Particularly, compound <b>23</b> stood out as the most potent, exhibiting not only the strongest anticancer activity with IC₅₀ values 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 against <i>Staphylococcus aureus</i> (<i>S. aureus</i>), <i>Bacillus subtilis</i> (<i>B. subtilis</i>), <i>Escherichia coli</i> (<i>E. coli</i>), and <i>Pseudomonas aeruginosa</i> (<i>P. aeruginosa</i>), respectively. Furthermore, compound <b>23</b> possessed the superior FtsZ inhibitory activity, facilitating polymerization. This was evident in the remarkably elongated cell morphology of <i>Bacillus subtilis</i> treated with compound <b>23</b>. To gain a deeper understanding of the underlying mechanisms, molecular docking studies were conducted, revealing the interaction mode between compound <b>23</b> and both tubulin and FtsZ, further elucidating its multifaceted biological activities. <b>Conclusions</b>: 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.