Patent Watch

October 1, 2012

Fight drug-resistant bacteria with gyrase and topo IV inhibitors. A. Le Tiran and co-inventors prepared compounds with structure 1 (Figure 1) that act as gyrase and/or topoisomerase IV (topo IV) inhibitors. In the structure, R is H or F, and X is H, −PO3H2–PO3HM+, −PO32–2M+, −PO32–D2+. M+ and D2+ are pharmaceutically acceptable monovalent and divalent cations, respectively.

Many of the compounds exhibit a broad range of antibacterial activities and have favorable toxicological properties. The compounds may become active ingredients or act as prodrugs of active compounds.

Bacterial DNA gyrase is a topoisomerase protein tetramer that consists of two A (GyrA) and two B (GyrB) subunits. GyrA is associated with binding and cleaving DNA, whereas GyrB binds and hydrolyzes ATP. Topo IV consists of the ATP-binding subunit ParE and the catalytic subunit ParC. It primarily resolves linked chromosome dimers at the conclusion of DNA replication.

Together, these enzymes are necessary for bacterial DNA replication, cell growth, and cell division. They are associated with DNA transcription, repair, and recombination. Inhibiting gyrase and/or topo IV is an attractive strategy for developing antibiotics with new mechanisms of action to battle emerging drug-resistant bacteria.

The inventors explain that GyrB and ParE subunits supply the necessary energy for catalytic turnover and for resetting enzymes via ATP hydrolysis. Inhibitors that target the ATP binding sites in the GyrB and the ParE subunits would be useful for treating various drug-resistant bacterial infections, including nosocomial (hospital-acquired) infections.

Using existing antibiotics as examples, the inventors state that the widely used quinolone and fluoroquinolone antibiotics that inhibit GyrA and/or ParC develop bacterial resistance. Another class of inhibitors is coumarin, one of the few antibiotics that bind to GyrB. Inhibiting it involves binding the coumarin carbonyl to the surface Arg136 unit in GyrB.

Coumarin-resistant bacteria have a mutation at that arginine residue. Enzymes with this mutation show lower supercoiling and ATPase activity, but they are also less sensitive to inhibition by coumarin drugs. Coumarins also do not penetrate bacteria well, and they show eukaryotic toxicity and poor water solubility.

Thus, it would be beneficial to introduce GyrB and ParE inhibitors that do not rely on binding to Arg136 for their activity. Such inhibitors would be antibiotic candidates that are unlikely to develop bacterial resistance.

The inventors prepared compounds 24 shown in Figure 2 and specifically claimed them in the patent application. They used the DNA gyrase ATPase assay to demonstrate their efficacy on Staphylococcus aureus DNA gyrase and S. aureus DNA topo IV. (Vertex Pharma [Cambridge, MA]. WIPO Publication WO2012097269, July 19, 2012; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

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