Bifunctional antibiotics

Details Bifunctional antibiotics Bifunctional antibiotics

2005-07-26

2005-07-26

Maier, Leigh C. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S017200, C514S025000

Reexamination Certificate

active

06921810

ABSTRACT:
Bifunctional antibiotics that target both bacterial RNA and resistance-causing enzymes are disclosed. The A-site of bacterial 16S rRNA serves as the target site for most aminoglycoside antibiotics. Resistance to this class of antibiotics is frequently developed by microbial enzymatic acetylation, phosphorylation or ribosylation of aminoglycosides, modifications that weaken their interactions with the target RNA. Using surface plasmon resonance (SPR), the binding affinity and stoichiometry of various amino-glycosides have been investigated and it was found that neamine, the key pharmacophore of the deoxystreptamine class of amino-glycosides, binds to the A-site in a two to one stoichiometry with a Kdof 10 μM for each binding site. A library of neamine dimers was prepared and their affinities to 16S rRNA A-site were determined by SPR, with Kd=40 nM for the best dimer (an ˜103-fold increase in affinity). Antibiotic activities of the dimers were determined for several bacterial strains by the Kirby-Bauer method. The most active dimer, based on antibiotic activity, also showed the highest inhibition of in vitro translation (IC50=0.055 μM). The latter assay was developed in order to correlate the relationship between SPR-based affinity and translation inhibition. By these combined methods, transport limitations for the semisynthetic aminoglycosides as well as non-ribosomally based antibiotic activity could be determined. Further analysis of these dimers as substrates for aminoglycoside modifying-enzymes identified a neamine dimer that was a potent inhibitor (Kis=0.1 μM) of the APH(2″) activity of the bifunctional enzyme AAC(6″)-APH(2″), the primary enzyme responsible for high level gentamicin C resistance in several bacterial strains.

REFERENCES:
Wang, H. et al. Bioorganic & Medicinal Chemistry Letters 1997, 7(14), 1951-1956.
Tok, J.B-H. et al. Bioorganic & Medicinal Chemistry Letters Jul. 17, 2000, 10, 1593-1595.
Sucheck, S.J. et al. J. Am. Chem. Soc. published on the Web May 16, 2000, 122, 5230-5231.
Patterson, et al., “High-Level Gentamicin Resistance inEnterococcus: Microbiology, Genetic Basis, and Epidemiology”,Rev. Infect. Diseases12: 644-652 (1990).
Edson, et al., “The Aminoglycosides”,Mayo Clin. Proc.66: 1158-1164 (1991).
Kondo, et al., “Semisynthetic aminoglycoside antibiotics: Development and enzymatic modifications”,J. Infect. Chemother.5: 1-9 (1999).
Moazed, et al., “Interaction of antibiotics with functional sites in 16S ribosomal RNA”,Nature327: 389-394 (1987).
Purohit, et al., “Interactions of a small RNA with antibiotic and RNA ligands of the 30S subunit”,Nature370: 659-662 (1994).
Sundram, et al., “Novel Vancomycin Dimers with Activity against Vancomycin-Resistant Enterococci”,J. Am. Chem. Soc.1996: 13107-13108 (1996).
Fourmy, et al., “Structure of the A Site ofEscherichia coli16S Ribosomal RNA Complexed with an Aminoglycoside Antibiotic”,Science274: 1367-1371 (1996).
Azucena, et al., “Properties of a Bifunctional Bacterial Antibiotic Resistance Enzyme That Catalyzes ATP-Dependent 2″-Phosphorylation and Acetyl-CoA-Dependent 6′-Acetylation of Aminoglycosides”,J. Am. Chem. Soc.119: 2317-2318 (1997).
Hendrix, et al., “Direct Observation of Aminoglycoside-RNA Interactions by Surface Plasmon Resonance”,J. Am. Chem. Soc.119: 3641-3648 (1997).
Rao, et al., “Tight Binding of a Dimeric Derivative of Vancomycin with Dimeric L-Lys-D-Ala-D-Ala”,J. Am. Chem. Soc.119: 10286-10290 (1997).
Wong, et al., “Specificity of aminoglycoside antibiotics for the A-site of the decoding region of ribosomal RNA”,Chem. Biol.5: 397-406 (1998).
Wright, et al., “Aminoglycoside Antibiotics: Structures, Functions, and Resistance”,Adv. Exp. Med. Biol.456: 27-69 (1998).
Mingeot-Leclerco, et al., “Aminoglycosides: Activity and Resistance”,Antimicrobial Agents and Chemotherapy43: 727-737 (1999).
Daigle, et al., “Prodigious substrate specificity of AAC(6′)-APH(2″), an aminoglycoside antibiotic resistance determinant in enterococci and staphylococci”,Chem. Biol.6: 99-110 (1999).
Greenburg, et al., “Design and Synthesis of New Aminoglycoside Antibiotics Containing Neamine as an Optimal Core Structure: Correlation of Antibiotic Activity with in Vitro Inhibition of Translation”,J. Am. Chem. Soc.121: 6527-6541 (1999).
Michael, et al., “Enhanced RNA Binding of Dimerized Aminoglycosides”,Bioorg. Med. Chem.7: 1361-1371 (1999).

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