Extended Data Fig. 6: Minodronate (MNDR) specifically targets S. pneumoniae farnesyl-PP synthase (SP_1205) and synergizes with vancomycin.
From: A bacterial pan-genome makes gene essentiality strain-dependent and evolvable
Growth of WT strains PG06 (in which SP_1205 is non-essential), TIGR4 and PG16 (in which SP_1205 is essential) and their derived SP_1205 knockouts in rich medium (SDMM), in the presence of non-inhibitory concentrations of vancomycin (VNC), in the presence or absence of the SP_1205 targeting drug MNDR, or both. Panels show the suppressor mutations that enable SP_1205 knockout in strains it is essential in. MNDR is a bisphosphonate drug currently in a phase-3 trial for human use, which targets human FPP synthase to suppress bone resorption and bone loss. However, there is evidence that bisphosphonates may also have antimicrobial potential75. The drug inhibits growth of the wild-type strains but not the SP_1205 knockouts. Because UP is critical for the cell wall, inhibition of UP synthesis may thus synergize with cell-wall synthesis inhibitors, like vancomycin. The combination of MNDR with vancomycin at a subinhibitory concentration has a synergistic effect on wild-type strains while there is no effect in ΔSP_1205 strains. Results shown are from n = 3 biologically independent samples per condition, independent repetition of each experiment (3) showed similar results. Error bars represent standard deviation.
