Composition for treatment of pathogens that are resistant to tetracyclines
Inventors
Schneider, Peter • Riedl, Rainer • Tigges, Marcel • Gitzinger, Marc • Pieren, Michel • Levi, Assaf • Sephton, Mark • Schellhorn, Birgit • Zueger, Patrik • Brand, Michael • Gygax, Daniel • Spies, Peter
Assignees
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Publication Number
US-9682079-B2
Publication Date
2017-06-20
Expiration Date
Abstract
The invention relates to compounds and pharmaceutical compositions useful in combination with tetracyclines in the treatment of bacterial infections caused by Gram-positive and Gram-negative pathogens, with particular efficacy in tetracycline resistant strains. These compounds specifically bind to TetR and therefore prevent the transcriptional activation of tet resistance genes. The compounds have a potentiating effect on the activity of members of the tetracycline family, in particular of tetracycline, minocycline, doxycycline and tigecycline, in the treatment of tetracycline susceptible, intermediate and tetracycline resistant pathogens.
Core Innovation
The invention relates to a pharmaceutical composition comprising one or more tetracyclines and a TetR binding compound. The TetR binding compound prevents TetR from dissociation of the tetO operator sequence in the presence of the inducing antibiotic tetracycline and is defined by a compound of formula (1) having substituent groups R1 to R6 and an integer parameter n.
The document addresses the problem that, in the presence of an inducing antibiotic tetracycline, TetR dissociates from the tetO operator sequence. The disclosed approach maintains TetR binding to the tetO operator sequence despite the presence of tetracyclines by using the specified TetR binding compound together with one or more tetracyclines.
The claim language further defines the TetR binding compound by allowed values for R1 and R2, independently selected options for R3 to R6, and restricted values of n. The description supports the specific compound embodiments described in the document.
Claims Coverage
The document includes two independent claim groups: a pharmaceutical-composition claim and a compound-of-formula claim. The inventive features focus on combining tetracyclines with a TetR binding compound that prevents TetR dissociation from the tetO operator sequence in the presence of an inducing tetracycline, and on defining that compound by formula (1) with specified substituent options and integer n constraints.
Tetracycline plus TetR binding compound preventing TetR dissociation from tetO
A pharmaceutical composition comprising one or more tetracyclines and a TetR binding compound preventing TetR from dissociation of the tetO operator sequence in the presence of the inducing antibiotic tetracycline.
TetR binding compound defined by formula (1) with restricted substituents and index n
The TetR binding compound is a compound of formula (1) wherein R1 is hydrogen or methyl, R2 is hydrogen or methyl, R3/R4/R5 are independently selected from specified groups, R6 is hydrogen, phenoxy or phenyl, and n is 1, 2, 3 or 4, with additional restrictions depending on R1.
Compound of formula (1) with restricted substituents and index n
A compound of formula (1) wherein R1 is hydrogen or methyl, R2 is hydrogen or methyl, R3 and R4 are independently hydrogen, lower alkyl, halo-lower alkyl, halogen, cyano, lower alkoxy, optionally substituted lower alkylcarbonylamino, or phenyl, R5 is hydrogen, methyl, trifluoromethyl, fluorine, chlorine or cyano, R6 is hydrogen, phenoxy or phenyl, and n is 3 or 4, or n is 1, 2, 3 or 4 if R1 is hydrogen.
Overall, the claim coverage centers on a TetR binding compound that maintains TetR association with the tetO operator sequence under inducing antibiotic tetracycline conditions, and on the specific structural definition of that compound via formula (1) with restricted R-group selections and integer n values.
Stated Advantages
Prevents TetR from dissociation of the tetO operator sequence in the presence of the inducing antibiotic tetracycline.
Enhances activity by preventing tetracycline-induced dissociation of TetR from the tetO operator sequence and blocking transcriptional activation of tet resistance genes.
Reduces MICs of tetracyclines in clinical tetracycline-resistant isolates, as reported using microdilution assays.
Documented Applications
Use in a pharmaceutical composition comprising one or more tetracyclines and a TetR binding compound for treating infective bacterial disease.
Treatment of infective bacterial disease by administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising one or more tetracyclines and a TetR binding compound that prevents TetR dissociation from the tetO operator sequence in the presence of the inducing antibiotic tetracycline.
A method of treatment of an infective bacterial disease comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to the pharmaceutical composition claim.
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