Search

Due to the rapid development of antimicrobial resistance, the discovery of new antibacterials is essential in the fight against potentially lethal infections. The DNA gyrase B (GyrB) subunit of bacterial DNA gyrase is an excellent target for the design of antibacterials, as it has been clinically validated by novobiocin. However, there are currently no drugs in clinical use that target GyrB. We prepared a new series of N-phenyl-4,5-dibromopyrrolamides and evaluated them against DNA gyrase and against the structurally and functionally similar enzyme, topoisomerase IV. The most active compound, 28, had an IC50 of 20 nM against Escherichia coli DNA gyrase. The IC50 values of 28 against Staphylococcus aureus DNA gyrase, and E. coli and S. aureus topoisomerase IV were in the low micromolar range. However, the compounds evaluated did not show significant antibacterial activities against selected Gram-positive and Gram-negative bacteria. Our results indicate that for potent inhibition of DNA gyrase, a combination of polar groups on the carboxylic end of the molecule and substituents that reach into the ''lipophilic floor'' of the enzyme is required. Članek objavljen 20. maja 2019. Abstract. Bibliografija: str. 1016-1017. ARRS Academy of Finland Academy of Finland Academy of Finland

ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9%nM against Escherichia coli DNA gyrase and 960%nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50%%M range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56%%M, 1.56%%M, 0.78%%M and 0.72%%M, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5%%M on both strains, and MIC value of 32%%M against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action. Bibliografija: str. 289-290. Abstract. ARRS Academy of Finland Academy of Finland Academy of Finland European Research Council, Resistance Evolution GINOP GINOP PhD fellowship from the Boehringer Ingelheim Fonds