Designing antibacterial Bi(III)-, Ga(III)- and Sb(III)-Thiosemicarbazone complexes to enhance lead compound development

The exploration of chemical space is crucial for advancing antibacterial drug discovery and developing novel therapeutic agents. We used a bismuth compound that restores carbapenem sensitivity in NDM-1-producing bacterial strains as a starting point to design a library of compounds through modifications of both the central metal core and ligand structure. The metal was substituted with other p-block metals like gallium(III) and antimony(III), while the ligand, a thiosemicarbazone, was derivatized, yielding a library of 16 compounds for biological evaluation. The synthesized compounds were tested for antimicrobial activity. Synergistic studies with resistant strains identified new lead compounds that restored antibiotic sensitivity. In vivo toxicity using Galleria mellonella larvae showed favorable safety profiles for several compounds. Despite strong in vitro activity, the compounds did not significantly improve survival rates in infected larvae, either as monotherapies or in combination with antibiotics. This study highlights the potential of rational lead compound modifications to identify novel antimicrobial agents.