Rapidly emerging antibiotic resistance to currently available antibiotics represents a serious threat to global human health, and thus novel classes of compounds that are active against both drug-sensitive and drug-resistant bacterial strains need to be identified. In this presentation, we report a novel class of antibacterial agents containing oligoamine linkers attached to either (bis)ureas or (bis)thioureas. Several representative oligoamines with linker lengths ranging from 3 to 7 carbons have been chemically attached to (bis)ureas or (bis)thiourea functionalities. The minimum inhibitor concentration (MIC) values of 18 terminally substituted (bis)urea or (bis)thiourea compounds range between 2 to 256 �g/ml. Interestingly, isosteric replacement of the central amine with a methylene unit results in complete loss of antibacterial activity thereby emphasizing the significance of two central cationic amine moieties. The terminal (bis)urea or (bis)thiourea moieties confer superior activity, as compared to the polyamines spermine (MIC >256 �g/ml) and spermidine (MIC >256 �g/ml). One of the most active compounds in the series, BP-107-5 (MIC 2 �g/ml) has greater antibacterial activity than gentamycin (MIC 8 �g/ml) or chloramphenicol (MIC 8 �g/ml). In the time-kill kinetics experiment, BP-107-5 exhibited a rapid, concentration-dependent killing of Pseudomonas aeruginosa (Pa), Escherichia coli (Ec) and Staphylococcus aureus (Sa) achieving a 6-log (99%) reduction in viable bacteria within 3 hours. When mixed with kanamycin, BP-107-5 produces a synergistic effect, whereas with norfloxacin it shows additive effects. Compound BP-107-5 displays selectivity of 5.3-fold against Pa, 16-fold against Ec and 5.3-fold against Sa when compared to cytotoxicity in normal kidney cells. Importantly, BP-107-5 displayed greater potency in biofilm inhibition and biofilm dispersal assays, in addition to being active against five clinical isolates of drug-resistant MRSA strains. Preliminary mechanistic studies suggest that BP-107-5 elicits antibiotic activity by causing membrane disruption. Overall, these results demonstrate that our compounds hold promise as a novel class of potent, broad-spectrum antibacterial agents with a unique mechanism of action.

Discovery of a novel class of potent, broad-spectrum antibacterial agents containing bis-thioureas and bis-ureas

248th National Meeting (2014)

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