Targeting the Prokaryotic-Specific GTP Cyclohydrolase-IB with Guanosine Analogs Toward a New Class of Antibiotics

GTP cyclohydrolase I (GCYH‐I) catalyzes the first step in the de novo biosynthesis pathway to folic acid in bacteria, biopterin synthesis in mammals, and the biosynthesis of 7‐deazaguanine modified nucleosides of tRNA in bacteria and archaea. The type IB GTP cyclohydrolase (GCYH‐IB) is a prokaryotic‐specific, essential enzyme found in several pathogens, including N. gonorrhoeae , and is structurally distinct from its human homologue GCYH‐IA involved in biopterin biosynthesis and thus has been proposed as a novel antibacterial drug target. Comparison of the crystal structures of the two enzymes bound to the substrate analog inhibitor 8‐oxo‐GTP shows that the active site of GCYH‐IB is larger and imposes a different conformation of the inhibitor. Based on this structural information, we designed, synthesized and tested a small set of 8‐oxo‐G derivatives with ether linkages expected to occupy water‐filled pockets present only in the active site of GCYH‐IB. The half maximal inhibitory concentrations, measured using standard GCYH‐I activity assays, are indicative of modest potency of these compounds. However, the most potent of these compounds, G3, is selective for GCYH‐IB. In silico molecular modeling of G3 in the active sites of both enzymes supports the observed preferential inhibition of the N. gonorrhoeaea enzyme by G3 on the grounds that it is too large to be accommodated by the active site of human GCYH‐IA. These results support the premise that potent and selective inhibitors of GCYH‐IB could constitute a new class of small molecule antibiotics. Support or Funding Information NIGMS grant GM110588 and GM132254 to M.A.S., and The California Metabolic Research Foundation (SDSU).