The research team led by Prof ANG Wee Han from the Department of Chemistry, NUS proposed a new approach to target bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit bacterial growth. Formate is an essential metabolite needed for growth in certain pathogenic strains but is only found in low amounts in mammalian cells. The researchers developed a molecular caging system for sulfonamide antibacterial drugs by replacing their essential amide function group with azide (N3–). They also found an aqueous-stable compound (organoruthenium complex) that can release these antibacterial drugs under certain conditions after screening through 768 unique ruthenium complexes (see Figure). When used together, the antibacterial drugs are released in the presence of endogenous formate found within bacterial cells. This strategy exploited formate, a necessary ingredient for bacterial growth, as a weapon to activate sulfonamide prodrugs using ruthenium complexes developed by the researchers.
Prof Ang said, “This is the first report that harnesses unique cellular metabolite to trigger prodrug activation in bacteria. It paves the way for a new approach of targeted antibacterial therapy by exploiting differences in the occurrence of natural metabolites among pathogenic strains.”
On the Figure above, (Left) A total of 768 (4 x 8 x 24) unique ruthenium complexes were generated via self-assembly reactions using molecular components A (4 types), B (8 types) and C (24 types) in aqueous solutions, then screened for transfer hydrogenation activities in presence of formate. Size of shaded circles denotes the efficacy of ruthenium complexes in carrying out transfer hydrogenation on the probe leading to fluorescence turn-on. Six possible candidates were identified. (Right) Antibacterial properties of prodrug P (red) in S. aureus and M. smegmatis was turned-on in the presence of Ru3 (blue) while supplementation of formate (green) had no effect on bacterial growth. Ru3, assembled using A4, B1 and C8, was able to utilise formate present in bacteria cells to activate P.
Read more about their new discovery here.
