New N -phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity

Abstract

The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC values against DNA gyrase, and submicromolar IC values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 μM against Enterococcus faecalis, and 3.13 μM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) is 4.6 μM.

An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors

“…Ala100 that is part of the flexible loop between amino acid residues Gly97-Ser108, as predicted by docking of compound 9d (IC50 = 6.9 nM) to the DNA gyrase B active site ( Figure 1S), and as reported by our research group for a related compound [15]. Interestingly, also some derivatives containing a combination of N-Boc-protected amino group and free carboxylic acid group on the right-hand side, e.g.…”

“…Design. Using our previous N-phenylpyrrolamide inhibitors as starting points [12][13][14][15], and having at disposal the crystal structure of E. coli GyrB in complex with one of our inhibitors (PDB code: 4ZVI) [12], optimised N-phenylpyrrolamides were prepared with improved on-target and antibacterial activities. The three structural types of compounds (types I-III, Figure 2) possess modifications on the central part and right-hand sides of the molecules.…”

“…The only ATPase inhibitor that has been used in the clinic is novobiocin, which was indroduced in the 1960s but was later withdrawn from the market due to its toxicity and weak potency [6,8]. More recently, 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.…”

Discovery of Furanoquinone Derivatives as a Novel Class of DNA Polymerase and Gyrase Inhibitors for MRSA Eradication in Cutaneous Infection

“…Furanoquinones exhibit a specific toxicity against MRSA with limited impact on humans. The dual inhibition of both enzymes further delays the occurrence of bacterial resistance because the simultaneous mutation on two targets is very low (Durcik et al, 2018). Topical administration of anti-MRSA agents for treating cutaneous infection have the advantages over oral or systemic counterparts of avoiding side effects, lowering cost, and decreasing drug resistance (Mohammad et al, 2015).…”

Systematic genome engineering approaches to investigate mutational effects and evolutionary processes

“…These results also have implications on the utility of previous laboratory evolutionary experiments of drug resistance which were performed in non-pathogenic, laboratory model strains. Also, analyses for novel antimicrobial agents [125,191].…”