Novel Combinations of DNAK Inhibitors With Known Antibacterial Agents

Abstract

Compositions, methods and kits are provided comprising (a) a therapeutically effective amount of a DnaK inhibitor; and (b) a therapeutically effective amount of a known antibacterial agent. Such compositions, methods and kits are useful in the treatment of various bacterial infections.

Description

FIELD OF THE INVENTION[0001]The invention relates generally to DnaK inhibiting agents. More specifically, the invention relates to natural peptide DnaK inhibitors, and analogs thereof, in combination with known antibacterial agents to elicit an enhanced inhibitory effect upon bacterial growth and / or bacteriocidal activity.BACKGROUND OF THE INVENTION[0002]The continuing search for new and effective antibacterial agents that can treat infections caused by organisms that are increasingly resistant to known classes of antibacterial agents has identified a plethora of potential next generation antibiotics. Many of these agents have subsequently been shown to demonstrate either poor physiochemical properties, an increased tendency to induce bacterial resistance, poor toxicological profiles, or low efficacy in vivo. Over the past decade or so, certain antibacterial peptides and glycopeptides isolated from insects have been noted as promising candidates for drug development programs (see, e...

AI Technical Summary

Benefits of technology

[0010]Applicants have invented compositions, methods, and kits for inhibiting the growth of bacteria comprising a DnaK inhibitor and a known antibacterial agent. Applicants have discovered that coadministration of such agents enhances the antibacterial potential of the DnaK inhibitor, the known antibacterial agent, or both. Such coadministration to patients suffering from a bacterial infection has the possible benefit of i) lowering the necessary therapeutically effective dose; ii) extending the duration of activity of a fixed dose; iii) reducing the likelihood of the development of resistant strains of the infecting organism; and / or iv) expanding the spectrum of activity of the individual agents. Agents that exhibit a therapeutic synergistic effect when coadministered are preferred.

[0014]In some embodiments, the DnaK inhibitor is pyrrhocoricin, drosocin or an analog thereof, while the known antibacterial agent is an antibiotic from the fluoroquinolone, β-lactam, tetracycline, macrolide, aminoglycoside, glycopeptide, or folic acid synthesis inhibitor family of antibiotics. Preferably, the DnaK inhibitor and antibiotic provide a therapeutic synergistic effect.

Problems solved by technology

Many of these agents have subsequently been shown to demonstrate either poor physiochemical properties, an increased tendency to induce bacterial resistance, poor toxicological profiles, or low efficacy in vivo.

While active in vitro, both drosocin and pyrrhocoricin are known to be highly susceptible to proteolytic degradation in the presence of mammalian serum.

While the role of the DnaK chaperone system in bacterial growth and survival is only now starting to be appreciated and understood, the role and utility of DnaK inhibitors as antibacterial agents is not well established.

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