New broad-spectrum and potent antibacterial agents with dual-targeting mechanism: Promoting FtsZ polymerization and disrupting bacterial membranes.

The emergence of multidrug-resistant bacteria and the slow development of new antibacterial agents have led to a growing global health crisis. Here, we identified an antibacterial agent possessing 1-methyl-2,5-diphenylpyridin-1-ium core, MA220607, with a dual-targeting mechanism of action (MOA), which exhibited effective killing activity against both Gram-positive (MIC = 0.062-2 μg/mL) and Gram-negative bacteria (MIC = 0.5-4 μg/mL). Moreover, our study revealed that MA220607 could block the formation of bacterial biofilm, which might be the reason for low frequency of resistance. MOA studies showed that MA220607 not only promoted FtsZ protein polymerization, but also increased the permeability of bacterial membranes and altered their proton gradients. In addition, MA220607 had low hemolytic toxicity and could significantly inhibit the growth of bacteria in mice. Molecular dynamics simulations demonstrated that MA220607 could block the transition from the tense (T) to relaxed (R) state of FtsZ protein, thereby perturbing the stepping mechanism of FtsZ protein. Overall, our findings suggest that integrating the dual mechanisms targeting FtsZ protein and cell membranes of bacteria into a single scaffold represents a promising direction for the development of new antibacterial agents.