Structure−Activity Relationships of Phenyl-Furanyl-Rhodanines as Inhibitors of RNA Polymerase with Antibacterial Activity on Biofilms

Abstract

The dramatic rise of antibiotic-resistant bacteria over the past two decades has stressed the need for completely novel classes of antibacterial agents. Accordingly, recent advances in the study of prokaryotic transcription open new opportunities for such molecules. This paper reports the structure-activity relationships of a series of phenyl-furanyl-rhodanines (PFRs) as antibacterial inhibitors of RNA polymerase (RNAP). The molecules have been evaluated for their ability to inhibit transcription and affect growth of bacteria living in suspension or in a biofilm and for their propensity to interact with serum albumin, a critical parameter for antibacterial drug discovery. The most active of these molecules inhibit Escherichia coli RNAP transcription at concentrations of </=10 microM and have promising activities against various Gram-positive pathogens including Staphylococcus epidermidis biofilms, a major cause of nosocomial infection.

Furanyl-Rhodanines Are Unattractive Drug Candidates for Development as Inhibitors of Bacterial RNA Polymerase

“…Compound 1 also lacked activity against Staphylococcus aureus and Bacillus subtilis (Table 4). We have no obvious explanation for the discrepancy between our data for compound 1 and the previously published results (15), especially since the structure of compound 1 (Table 1) was confirmed by full spectroscopic analysis (see the supplemental material) to be the same as that previously examined (15). In contrast to the results for compound 1, we confirmed that the other two furanyl-rhodanines (compounds 2 and 3) reported to possess antibacterial activity (4, 16) did indeed prevent the growth of S. aureus, B. subtilis, and E. coli (Table 4).…”

“…However, it is underexploited, since the rifamycins are the only RNAP inhibitors that have been developed for clinical use (2,8,14). Recently several furanyl-rhodanines that apparently possess antibacterial activity and inhibit Escherichia coli (RNAP) were described (15). This series had been expanded from a compound considered to be a specific RNAP inhibitor on the basis of cross-screening against unrelated enzymes and failure to inhibit in an in vitro transcription-translation assay using a reticulocyte lysate (15).…”

“…Recently several furanyl-rhodanines that apparently possess antibacterial activity and inhibit Escherichia coli (RNAP) were described (15). This series had been expanded from a compound considered to be a specific RNAP inhibitor on the basis of cross-screening against unrelated enzymes and failure to inhibit in an in vitro transcription-translation assay using a reticulocyte lysate (15). In view of our interest in RNAP inhibitors (1, 2, 10), we decided to examine in more detail compound 1 (Table 1), the most potent of the recently identified furanyl-rhodanine RNAP inhibitors (15).…”

“…This series had been expanded from a compound considered to be a specific RNAP inhibitor on the basis of cross-screening against unrelated enzymes and failure to inhibit in an in vitro transcription-translation assay using a reticulocyte lysate (15). In view of our interest in RNAP inhibitors (1, 2, 10), we decided to examine in more detail compound 1 (Table 1), the most potent of the recently identified furanyl-rhodanine RNAP inhibitors (15). We also considered whether other furanyl-rhodanines (compounds 2 and 3 in Table 1) reported to possess antibacterial activity (4, 16) might also be inhibitors of RNAP.…”

“…Compounds 1 to 3 are reported to possess antibacterial activity (4,15,16). We therefore sought to examine their modes of action and in particular to elucidate whether inhibition of bacterial growth might be attributed to inhibition of RNAP activity within the whole cell.…”