Bifunctional antibiotics for targeting rRNA and resistance-causing enzymes and for inhibition of anthrax lethal factor

Abstract

A novel group of aminoglycosides which share some structural features of currently available aminoglycosides with regard to the backbone, while also having significant structural differences, is disclosed. The similarity enables these aminoglycosides to be highly potent and effective antibiotics, while the significant differences enable these aminoglycosides to reduce or even block antibiotic resistance. The aminoglycosides of the present invention are suitable for inhibition of antrax lethal factor, hence are suitable for use as a cure for anthrax.

Description

[0001] This application is a continuation-in-part of PCT Patent Application No. PCT / IL2004 / 000490, filed Jun. 9, 2004, which claims priority from U.S. Pat. application Ser. No. 10 / 829,976, filed Apr. 23, 2004, and U.S. Provisional Patent Applications Nos. 60 / 540,359, filed Feb. 2, 2004, and 60 / 484,293, filed Jul. 3, 2003. This application also claims the benefit of priority from U.S. Provisional Patent Application No. 60 / 608,372, filed Sep. 10, 2004. The teachings of the above applications are hereby incorporated by reference as if fully set forth herein.FIELD OF THE INVENTION [0002] The present invention relates to bi-functional antibiotics, and in particular to aminoglycosides which are capable of reducing the efficacy of and / or blocking antibiotic resistance. The aminoglycosides of the present invention are suitable for inhibition of anthrax lethal factor, hence are suitable for use as a cure for anthrax. BACKGROUND OF THE INVENTION [0003] The rapid spread of antibiotic resistanc...

AI Technical Summary

Benefits of technology

[0012] The present invention overcomes the deficiencies of the prior art by providing a novel group of aminoglycosides which share some structural features of currently available aminoglycosides with regard to the backbone, while also having significant structural differences. The similarity enables these aminoglycosides to be highly potent and effective antibiotics, while the significant differences enable these aminoglycosides to reduce or even block antibiotic resistance. These aminoglycosides are highly effective for treatment of anthrax.

[0057] Without wishing to be limited by a single hypothesis, the present invention is believed to have better stability and greater resistance to bacterial enzymes for a number of reasons, including the optional presence of a thiol moiety at X, which is more resistant to hydrolysis. The presence of a monosaccharide or oligosaccharide at R1 also increases resistance to hydrolysis. Again without wishing to be limited by a single hypothesis, resistance to hydrolysis is also believed to decrease toxicity, as the compounds of the present invention are expected to hydrolyze within the body (outside of bacterial cells) at a lower rate, and hence to potentially produce fewer toxic degradation products.

[0068] Another object of the invention is to provide bifunctional antibiotics which reduce or eliminate antibiotic resistance and which further result in reduction of cytoxicity and other side-effects.

Problems solved by technology

Indeed, microbiologists today warn of a “medical disaster” which could lead back to the era before penicillin, when even seemingly small infections were potentially lethal.

However, this approach is both time-consuming and financially prohibitive, yet remains indispensable if an acceptable level of care is to be provided in the immediate future.

Unfortunately, prolonged clinical use of currently available aminoglycosides has resulted in effective selection of resistance to this family of antibacterial agents (9).

Presently, resistance to these agents is widespread among pathogens worldwide which severely limits their usefulness.

Through a mechanism that is not yet well understood, this results in the death of the host.

The prior art does not teach or suggest a highly effective group of aminoglycosides which both share certain structural features of currently available aminoglycosides while also being able to reduce or eliminate antibiotic resistance.

The prior art also does not teach or suggest such aminoglycosides which have reduced side effects.

The prior art also does not teach or suggest such aminoglycosides which are capable of functioning both by inhibition of anthrax lethal factor, and as an antibiotic and are therefore highly effective for treatment of anthrax.

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