Isoprenoid Reductase Could Become Target for Novel Antimicrobials

An unusual enzyme reaction mechanism that appears vital for malaria parasites and microbial pathogens but not mammalian species could prove a useful target for novel antimicrobial agents, according to chemist Eric Oldfield of the University of Illinois (UI), Champaign-Urbana, and his collaborators.  To emphasize that point, they identified a potent inhibitor of the reductase reaction-an alkyne diphosphate-that appears to inhibit that enzyme much like acetylene inhibits the bacterial enzyme nitrogenase. Whether the novel inhibitor acts in vivo remains to be determined, but it is "1,000 times more potent than previous inhibitors," he says. "Much work remains to be done to develop antimalarial or antibacterial drugs based on the new findings."

The enzyme in question, a reductase called IspH, presides over a series of biosynthetic reactions that produce essential isoprenoids, a family of molecules that includes _-carotene, cholesterol, and critical building blocks of some microbial cell walls, according to Oldfield. In malaria parasites, for instance, isoprenoids are components of potentially disruptable signaling cascades, he says. IspH is unusual for having a cube-shaped core of four iron and four sulfur atoms, and for forming a highly unusual iron-carbon bond with its substrate.

The electron paramagnetic resonance spectra for IspH and inhibitors proved similar to those for another bacterial enzyme, nitrogenase, which, like IspH, has a metal-sulfur core and acts as a reductase. Knowing that acetylene inhibits nitrogenase, the UI researchers sought a similar compound to inhibit IspH. PPP, the acetylene derivative that they developed, proves highly potent, according to Oldfield. "When combined with our spectroscopic results and the results of quantum mechanical calculations, we will gain unprecedented insights into how these proteins function," he says.

"We can expect that their discovery will lead to intense follow-up studies because the results have obvious implications for both biomedicine and organometalic catalysis," says Thomas B. Rauchfuss, also at UI, who is not involved in the study by Oldfield and his collaborators. "Iron-sulfur clusters are found in all forms of life, so when a new function is discovered, it is big news to a wide community."

The IspH mechanism is at the front end of "a pathway used by malaria parasites and most pathogenic bacteria," says Roberto Docampo of the University of Georgia, Athens, who was not involved in the UI research. "These results will lead to new types of drugs of potential use in medicine." Despite their virtues, however, the development of IspH inhibitors also could lead to development of resistance to those inhibitors, he adds.

Thus, for example, mutations can develop in genes encoding IspH leading directly to resistance to its inhibitors or microorganisms treated with such inhibitors might produce proteins that pump them from cells.

Nonetheless, the UI research on IspH inhibitors "is a beautiful blend of inorganic, organic, and medicinal chemistry," says Andrew McCammon of the University of California, San Diego. Both he and Docampo agree that the UI findings "break new ground." Details of the UI research appear in Proceedings of the National Academy of Sciences, 2010 107:4522-4527; published online before print February 19, 2010, doi:10.1073/pnas. b0911087107

David C. Holzman