Eis inhibitors
Inventors
Garneau-Tsodikova, Sylvie • Tsodikov, Oleg V. • Posey, James E.
Assignees
University of Kentucky Research Foundation • US Department of Health and Human Services
Publication Number
US-10208000-B2
Publication Date
2019-02-19
Expiration Date
2036-12-16
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Abstract
Provided herein are novel small-molecules that have use in the inhibition of Eis, which mediates kanamycin resistance in Mycobacterium tuberculosis. The presently-disclosed subject matter further includes a pharmaceutical composition including a small molecule inhibitor, as described herein, and a suitable pharmaceutical carrier. Methods of treating tuberculosis comprising administering to an individual an effective amount of the disclosed small molecule inhibitors to mediate kanamycin A resistance and treat tuberculosis are also provided.
Core Innovation
The invention provides novel small-molecule inhibitors of acetyltransferase Eis, which is a mediator of kanamycin resistance in Mycobacterium tuberculosis (Mtb). In particular, the compositions include sulfonamide-based and sulfonyl isothiazole-based small molecules. These inhibitors can effectively overcome kanamycin resistance in strains of Mtb and are used in pharmaceutical compositions and methods of treatment, including administration with aminoglycosides such as kanamycin (KAN).
The problem being solved addresses the major health threat posed by tuberculosis (TB), particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, where resistance to aminoglycosides like kanamycin arises through upregulation of Eis, an acetyltransferase that inactivates these antibiotics by multiacetylation. Current treatments are compromised by Eis-mediated drug resistance, and prior approaches to develop Eis inhibitors have been limited. Thus, the invention provides Eis inhibitors that sensitize resistant Mtb strains to kanamycin and restore its antibacterial activity, enabling novel combination therapies to combat resistant TB.
Claims Coverage
The patent claims cover multiple inventive features relating to compounds, compositions, methods of inhibition, treatment methods, and kits involving Eis inhibitors.
Compound structure as Eis inhibitor
A compound of a specified chemical formula that functions as an inhibitor of the Eis acetyltransferase enzyme in Mycobacterium tuberculosis.
Pharmaceutical composition with Eis inhibitor and carrier
A pharmaceutical composition comprising the Eis inhibitor compound and a suitable pharmaceutical carrier.
Pharmaceutical composition further comprising an aminoglycoside
A pharmaceutical composition including the Eis inhibitor compound, a suitable pharmaceutical carrier, and an aminoglycoside antibiotic.
Use of kanamycin as the aminoglycoside in the composition
The pharmaceutical composition wherein the aminoglycoside included is specifically kanamycin (KAN).
Method of inhibiting Eis by administering the inhibitor composition
Administering to a subject an effective amount of a composition comprising the Eis inhibitor compound to inhibit Eis enzymatic activity.
Administration method with specific compound formulas
Administering an effective amount of a composition comprising particular Eis inhibitor compounds according to formulas disclosed.
Method achieving specified MIC values for kanamycin susceptibility
Administering the Eis inhibitor compound results in reducing the Minimum Inhibitory Concentration of kanamycin (MICKAN) to less than about 0.625 μg/mL for Mtb H37Rv or less than about 5 μg/mL for Mtb K204.
Method including aminoglycoside administration with Eis inhibitor
The method of treating Eis inhibition further comprising administering an aminoglycoside antibiotic.
Use of kanamycin in combination with Eis inhibitor for treatment
The aminoglycoside administered in combination with the Eis inhibitor is kanamycin (KAN).
Method of treating aminoglycoside-resistant Mycobacterium tuberculosis
Administering the Eis inhibitor compound to a subject to treat aminoglycoside-resistant Mycobacterium tuberculosis infection.
Combination therapy with aminoglycoside for resistant Mtb treatment
Administering the Eis inhibitor compound together with an aminoglycoside, including kanamycin, to a subject in need to treat resistant Mtb.
Kit comprising the Eis inhibitor compound and aminoglycoside
A kit containing the Eis inhibitor compound packaged together with an aminoglycoside antibiotic.
Kit specifically containing kanamycin as the aminoglycoside
The kit where the aminoglycoside included is specifically kanamycin (KAN).
The claims cover chemical compounds as Eis inhibitors, pharmaceutical compositions including these compounds alone or with aminoglycosides like kanamycin, methods of administering these compounds for inhibiting Eis and treating resistant tuberculosis, and kits comprising these components.
Stated Advantages
The Eis inhibitors can effectively overcome kanamycin resistance in strains of Mtb.
The inhibitors bind in the aminoglycoside (AG) binding pocket of Eis, blocking access of AGs to the active site of the enzyme.
Binding of the inhibitors induces conformational changes in Eis, providing a foundation for structure-based drug development.
The small molecule Eis inhibitors allow restoration of kanamycin susceptibility in resistant Mtb strains.
The combination therapies utilizing Eis inhibitors and kanamycin can prevent emergence of new resistant strains by mutagenesis of the eis promoter.
Documented Applications
Use of the Eis inhibitors in pharmaceutical compositions for the treatment of tuberculosis, including aminoglycoside-resistant tuberculosis.
Combination therapy involving administration of Eis inhibitors and aminoglycosides, such as kanamycin, to treat kanamycin-resistant Mycobacterium tuberculosis infections.
Inhibiting Eis enzymatic activity in bacteria to restore the efficacy of aminoglycoside antibiotics.
Use of kits comprising Eis inhibitors packaged with aminoglycosides for therapeutic applications against drug resistant TB.
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