New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine

Cyclothialidine (<BO>1</BO>, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of <BO>1</BO>, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure−activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (<BO>X</BO>) of <BO>1</BO> seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (<BO>XI</BO>). On the basis of these “minimal structures” a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (<BO>94</BO>, <BO>97</BO>), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (<BO>1</BO>) that showed efficacy in vivo.