Identification, evolution, and essentiality of the mevalonate pathway for isopentenyl diphosphate biosynthesis in gram-positive cocci

The mevalonate pathway and the glyceraldehyde 3-phosphate (GAP)-pyruvate pa thway are alternative routes for the biosynthesis of the central isoprenoid precursor, isopentenyl diphosphate. Genomic analysis revealed that the sta phylococci, streptococci, and enterococci possess genes predicted to encode all of the enzymes of the mevalonate pathway and not the GAP-pyruvate path way, unlike Bacillus subtilis and most gram-negative bacteria studied, whic h possess only components of the latter pathway. Phylogenetic and comparati ve genome analyses suggest that the genes for mevalonate biosynthesis in gr am-positive cocci, which are highly divergent from those of mammals, were h orizontally transferred from a primitive eukaryotic cell. Enterococci uniqu ely encode a bifunctional protein predicted to possess both 3-hydroxy-3-met hylglutaryl coenzyme A (HMG-CoA) reductase and acetyl-CoA acetyltransferase activities. Genetic disruption experiments have shown that five genes enco ding proteins involved in this pathway (HMG-CoA synthase, HMG-CoA reductase , mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate d ecarboxylase) are essential for the in vitro growth of Streptococcus pneumo niae under standard conditions. Allelic replacement of the HMG-CoA synthase gene rendered the organism auxotrophic for mevalonate and severely attenua ted in a murine respiratory tract infection model. The mevalonate pathway t hus represents a potential antibacterial target in the low-G+C gram-positiv e cocci.