In vitro susceptibility of cultured human methanogens to lovastatin

Abstract

Lovastatin is a prodrug that is hydrolysed in vivo to β-hydroxy acid lovastatin, which inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co-A) reductase (HMGR), thereby lowering cholesterol in humans. A side effect of lovastatin is inhibition of isoprenoid synthesis and cell membrane formation in methanogenic Archaea, which are members of the human digestive tract microbiota and are emerging pathogens. In this study, the in vitro susceptibility of the human-associated methanogens Methanobrevibacter smithii, Methanobrevibacter oralis, Methanobrevibacter massiliense, Methanobrevibacter arboriphilus and Methanomassiliicoccus luminyensis to lovastatin (1–4 µg/mL) was tested in the presence of five gut anaerobes aiming to metabolise lovastatin into β-hydroxy acid lovastatin as confirmed by ultra-high-performance liquid chromatography. Five days of incubation with lovastatin had no measurable effect on the growth of the five gut anaerobes but significantly reduced CH4 production and methanogen growth as measured by quantitative PCR (P < 0.01). Quantitative PCR analyses indicated that compared with controls, β-hydroxy acid lovastatin significantly increased the expression of the genes mta and mcrA implicated in methanogenesis and significantly decreased the expression of the fno gene implicated in methanogenesis. Expression of the HMGR gene (hmg) implicated in cell wall synthesis was significantly increased by β-hydroxy acid lovastatin (P < 0.01). These results strongly suggest that in the presence of gut anaerobes, lovastatin yields β-hydroxy acid lovastatin, which inhibits methane production and growth of methanogens by affecting their cell membrane biosynthesis. Lovastatin is the first licensed drug to exclusively affect the growth of methanogens whilst protecting the bacterial microbiota.