Abstract
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 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, 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 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.
Highlights
Antibiotic-resistant infections kill an estimated 700,000 people each year [1]
Our goal was to prepare a molecular hybrid in which the left-hand side of the molecule is represented by the N-phenylpyrrolamide DNA gyrase B-binding motif, and the right-hand side is represented by the 4-oxo-quinoline-2-carboxlic acid moiety, a known DNA gyrase A binder (Figure 3)
We have designed and prepared a series of new N-phenylpyrrolamides as DNA gyrase and topoisomerase IV inhibitors interacting with the ATP binding site
Summary
Antibiotic-resistant infections kill an estimated 700,000 people each year [1]. Recently, the World Health Organization (WHO) has issued a list of drug-resistant bacteria that pose the greatest threat to human health and present a big challenge for antibacterial drug development. DNA gyrase and topoisomerase IV belong to type II topoisomerases and display high structural and functional similarities They are both heterotetrameric enzymes composed of two pairs of subunits. DNA gyrase is composed of two GyrA and two GyrB subunits, while topoisomerase IV is composed of two ParC and two ParE subunits. GyrA and GyrB subunits of DNA gyrase are similar in amino acid sequence to ParC and ParE subunits of topoisomerase IV, respectively [5]. The first is stabilisation of the covalent enzyme–DNA complex, i.e. gyrase poisoning This mechanism is typical of the quinolone class of antibacterials, with ciprofloxacin as the most distinctive representative. The growing resistance problem together with some serious side effects has stimulated the search for new inhibitors which target ATP binding site on DNA gyrase and topoisomerase IV. Many structurally diverse classes of GyrB inhibitors have been discovered, such as pyrrolamides [9], benzothiazoles [10], ethyl ureas [11], N-phenylpyrrolamides [12,13,14,15] and pyrimidoindoles [16] (Figure 1), which possess potent on-target and antibacterial activities but have some liabilities, such as unfavourable physicochemical properties or toxicity issues
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