Inhibitors of the Mevalonate Pathway of Streptococcus Pneumoniae

NU 2006-166

Inventors

Richard Silverman*

Takashi Kudoh

Abstract

Northwestern researchers have identified a new strategy for treating the human pathogen Streptococcus pneumoniae using diphosphomevalonate (DPM)-based antibiotics. Unlike the human mevalonate pathway, S. pneumonia is regulated by DPM, making the bacterial pathway an attractive antibiotic target. As the penultimate compound in the mevalonate pathway, DPM is critical for the isoprenoid biosynthetic pathway, which is essential for the survival of the pathogen. Since DPM itself possesses poor drug characteristics being highly charged, the investigators have targeted this pathway using a prodrug strategy. In fact, they have established the feasibility of using such a prodrug strategy for DPM using unphosphorylated and cell-permeable mevalonate analogues, which are subsequently phosphorylated by endogenous MK and phosphomevalonate kinase (PMK) and ultimately generate active compounds in situ. The researchers have synthesized a series of substituted mevalonate analogues targeting the MK and PMK active sites, which may serve as either competitive or noncompetitive reversible inhibitors of MK and related pathway enzymes. Compositions that may act as mechanism-based inactivators of the next enzyme in the pathway were also identified.

Applications

• Therapeutics: Streptococcus pneumoniae

Advantages

• Established feasibility of using a prodrug strategy for DPM-based antibiotics in S. pneumonia
• Identification of several analogues as potential inhibitors of MK

Publications

Kudoh T, Park CS, Lefurgy ST, Sun M, Michels T Leyh TS and Silverman RB (2010) Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae. Bioorganic & Medicinal Chemistry. 18: 1124-1134.

IP Status

A patent application has been filed.