Head-to-Head Prenyl Tranferases: Anti-Infective Drug Targets

We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from <i>Staphylococcus aureus</i>: <b>1</b> (BPH-651), <b>2</b> (WC-9), and <b>3</b> (SQ-109). Compound <b>2</b> binds to the S2 site with its −SCN group surrounded by four hydrogen bond donors. With <b>1</b>, we report two structures: in both, the quinuclidine headgroup binds in the allylic (S1) site with the side chain in S2, but in the presence of PPi and Mg²⁺, the quinuclidine’s cationic center interacts with PPi and three Mg²⁺, mimicking a transition state involved in diphosphate ionization. With <b>3</b>, there are again two structures. In one, the geranyl side chain binds to either S1 or S2 and the adamantane headgroup binds to S1. In the second, the side chain binds to S2 while the headgroup binds to S1. These results provide structural clues for the mechanism and inhibition of the head-to-head prenyl transferases and should aid future drug design

HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis

We report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (UPPS) and dehydrosqualene synthase (CrtM). The leads were suggested by the observation that keto- and diketo-acids bind to the active site Mg²⁺/Asp domain in HIV-1 integrase, and similar domains are present in prenyl transferases. We report the X-ray crystallographic structures of one diketo-acid and one keto-acid bound to CrtM, which supports the Mg²⁺ binding hypothesis, together with the X-ray structure of one diketo-acid bound to UPPS. In all cases, the inhibitors bind to a farnesyl diphosphate substrate-binding site. Compound <b>45</b> had cell growth inhibition MIC₉₀ values of ∼250–500 ng/mL against <i>Staphylococcus aureus</i>, 500 ng/mL against <i>Bacillus anthracis</i>, 4 μg/mL against <i>Listeria monocytogenes</i> and <i>Enterococcus faecium</i>, and 1 μg/mL against <i>Streptococcus pyogenes</i> M1 but very little activity against <i>Escherichia coli</i> (DH5α, K12) or human cell lines