Leprosy is a chronic infectious disease caused by Mycobacterium leprae and M. lepromatosis . Brazil consistently ranks among the countries with the highest number of leprosy cases. Data from our group showed that M. leprae upregulates the mevalonate pathway (MP), contributing to the accumulation of cholesterol-ester-enriched lipid droplets in infected macrophages, and that the inhibition of this pathway by statins decreases bacterial intracellular viability. It has already been shown that part of the deleterious effect of statins on M. leprae survival is related to the reduced cholesterol levels, which M. leprae oxidizes to generate reductive power. According to the literature, statins, by inhibiting MP, increase the production of the inflammatory cytokine IL-1β through the negative modulation of the biosynthesis of the isoprenoid geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), which are responsible for protein prenylation. In the present study, we tested the hypothesis that part of the effect of statins on the intracellular viability of M. leprae comes from their impact on IL-1β production via decreased prenylation. We demonstrate that GGPP is essential in macrophage –M. leprae interaction since the MP inhibitors, pamidronate and GGTI-298, which inhibit the enzymes farnesyl pyrophosphate synthase and geranylgeranyl transferase-1, respectively, decreased the intracellular viability of M. leprae , measured by RT-qPCR. MP inhibitors increased IL-1β production by activating the inflammasome, but this effect was reversed with GGPP. IL-1β levels were inversely related to bacterial survival. In conclusion, our findings highlight the potential role of protein geranylgeranylation in M. leprae pathogenesis and suggest new therapy options for leprosy.
BT - Journal of Bacteriology DO - 10.1128/jb.00185-25 IS - 9 LA - ENG M3 - Article N2 -Leprosy is a chronic infectious disease caused by Mycobacterium leprae and M. lepromatosis . Brazil consistently ranks among the countries with the highest number of leprosy cases. Data from our group showed that M. leprae upregulates the mevalonate pathway (MP), contributing to the accumulation of cholesterol-ester-enriched lipid droplets in infected macrophages, and that the inhibition of this pathway by statins decreases bacterial intracellular viability. It has already been shown that part of the deleterious effect of statins on M. leprae survival is related to the reduced cholesterol levels, which M. leprae oxidizes to generate reductive power. According to the literature, statins, by inhibiting MP, increase the production of the inflammatory cytokine IL-1β through the negative modulation of the biosynthesis of the isoprenoid geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), which are responsible for protein prenylation. In the present study, we tested the hypothesis that part of the effect of statins on the intracellular viability of M. leprae comes from their impact on IL-1β production via decreased prenylation. We demonstrate that GGPP is essential in macrophage –M. leprae interaction since the MP inhibitors, pamidronate and GGTI-298, which inhibit the enzymes farnesyl pyrophosphate synthase and geranylgeranyl transferase-1, respectively, decreased the intracellular viability of M. leprae , measured by RT-qPCR. MP inhibitors increased IL-1β production by activating the inflammasome, but this effect was reversed with GGPP. IL-1β levels were inversely related to bacterial survival. In conclusion, our findings highlight the potential role of protein geranylgeranylation in M. leprae pathogenesis and suggest new therapy options for leprosy.
PB - American Society for Microbiology PY - 2025 SP - 1 EP - 17 T2 - Journal of Bacteriology TI - Impact of protein prenylation inhibition on Mycobacterium leprae viability and IL-1β production in infected macrophages UR - https://journals.asm.org/doi/pdf/10.1128/jb.00185-25?download=true VL - 207 SN - 0021-9193, 1098-5530 ER -