Repurposing a Serotonin Receptor Antagonist as a Potential Novel Antibiotic

With the surge of multidrug-resistant bacteria and increasing antibiotic resistance, there is a critical need for the development of new drug therapies. A new antimicrobial technique revolves around targeting virulence factors, which enable the bacterial pathogen to evade host immune defenses. Inhibitors that target pathogenicity hinder the capacity of the bacterium to cause an infection, thus allowing the host immune system to better clear the infection. In this study, we aim to inhibit the ClpXP protease, a highly conserved intracellular protease involved in the virulence in different bacterial pathogens. Previous studies have shown that loss of ClpX completely attenuates virulence in Bacillus anthracis, rendering the pathogen more susceptible to cell envelope targeting antibiotics, such as penicillin, daptomycin, and LL-37. Computational modeling was performed, and ten commercially available inhibitors with predicted activity against the ClpXP protease were identified, with ritanserin showing the most promise. In this study, we explore the antimicrobial effects of ritanserin, a previously identified serotonin 2A receptor antagonist that underwent clinical trials as a potential treatment for depression, schizophrenia, and substance dependence. We hypothesized that if ritanserin inhibits ClpXP formation in B. anthracis Sterne, it should mimic the phenotype of the knockout clpX mutant, ΔclpX. We found that ritanserin increased WT Bacillus anthracis susceptibility to the cell envelope targeting antibiotics penicillin and daptomycin. Future studies showed increased susceptibility to host defenses, such as antimicrobial peptides, including LL-37. This demonstrates that ritanserin could be potentially repurposed as an antibacterial drug with the potential to be used by itself or in combination with antibiotics.