Structure-Based Docking Analysis of FDA Approved Antibiotics Targeting LipL32 Protein as a Potential Therapeutic Approach Against Leptospirosis

Background: Leptospirosis is a globally re-emerging zoonotic disease associated with significant morbidity and mortality, particularly in tropical and subtropical regions. LipL32, the most abundant and conserved outer membrane lipoprotein of pathogenic Leptospira spp., plays a central role in host tissue adhesion through extracellular matrix (ECM) interactions. Given its structural and adhesion-mediating function rather than enzymatic activity, LipL32 represents a promising target for interaction-disruption strategies. Drug repurposing of FDA-approved antibiotics offers a rapid and costeffective approach for identifying novel therapeutic candidates. Objective: To investigate a possible interference of metronidazole with central monoaminergic mechanisms using the Forced Swim Test. Methods: To assess the binding potential of FDA-approved antibiotics on LipL32 protein (PDB ID: 3FRL) with molecular docking based on the structure and to prioritize the candidates to be repurposed in the treatment of leptospirosis. Results: Norfloxacin, meclocycline, and cloxacillin emerged as top candidates with strong binding affinities of −9.4, −8.3, and −8.3 kcal/mol, respectively. Detailed interaction analysis revealed that these antibiotics form key hydrogen bonds and hydrophobic contacts with critical LipL32 residues, potentially disrupting its ability to bind extracellular matrix components. Conclusion: Supporting evidence from previous studies suggests that norfloxacin may exert dual actions by inhibiting LipL32 expression and modulating host immune responses. These findings highlight the potential of drug repurposing strategies in combating leptospirosis and advocate for further in vitro and in vivo investigations to validate the therapeutic efficacy of these antibiotics. In addition to docking affinity ranking, comparative benchmarking against standard-of-care agents, interaction hotspot mapping, and pharmacokinetic profiling, it incorporated a translationally oriented prioritization strategy for LipL32, a target for drug repurposing.