Inhibitors of bacterial pasta kinases
Inventors
Striker, Robert Todd • Wlodarchak, Nathan Joseph • Feltenberger, John Bruce • Golden, Jennifer
Assignees
US Department of Veterans Affairs • Wisconsin Alumni Research Foundation
Publication Number
US-11820753-B2
Publication Date
2023-11-21
Expiration Date
2041-02-10
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Abstract
Biochemically active PASTA kinase inhibitors which exploit subtle structural differences between human kinases and bacterial PASTA kinases to improve specificity and inhibitor activity. The disclosed kinase inhibitors have the general formula: wherein: R1=Me, Et, n-Pr, —CH2CH2OH, —CH2CH2OP(O)(OH)2, —CH2CH2NMe2;R2=H, Me, Et, o-Pr, i-Pr, CF3, Cl, OMe;R3=H, Me, NHMe, NHBn, Cl, NO2OMe, F, CN; andAr=
Core Innovation
The invention discloses biochemically active PASTA kinase inhibitors that exploit subtle structural differences between human kinases and bacterial PASTA kinases to improve specificity and inhibitor activity. These inhibitors have a general chemical formula with variable substitutions (R1, R2, R3, and Ar groups) designed to target bacterial kinases more selectively, particularly Penicillin-binding And Serine/Threonine Associated (PASTA) kinases such as PknB.
The problem being addressed arises from the growing worldwide threat of antibiotic-resistant pathogens, especially Gram-positive bacteria like Mycobacterium tuberculosis and Staphylococcus aureus, which have limited treatment options and increasing resistance to existing antibiotics. Current antibiotics target a narrow range of bacterial processes but do not target bacterial signal transduction pathways mediated by protein kinases. There is a long-felt need for new therapeutic compounds that target bacterial kinases to treat these resistant infections effectively.
The invention improves specificity and activity by modulating inhibitor moieties positioned in the back pocket of the kinase active site and exploiting differences in PASTA kinase ATP binding floors. The compounds provide a new and effective treatment approach for difficult-to-treat human pathogens, particularly through inhibition of bacterial PASTA kinases such as PknB, which are essential for bacterial survival and growth.
Claims Coverage
The patent contains multiple independent claims covering compounds, methods of kinase inhibition, and methods of treating bacterial infections with specific inventive features.
Compound for selective inhibition of bacterial protein kinases
A compound having a chemical structure comprising variable substituents R1, R2, R3, and Ar groups designed for selective inhibition of a protein kinase in a bacterium, particularly targeting PASTA kinases such as PknB.
Method of inhibiting protein kinase using the compound
Administering an effective amount of the described compound to a subject, thereby inhibiting protein kinase activity within the subject, including specific inhibition of PASTA kinases like PknB.
Method of treating bacterial infections with the compound
Administering an effective amount of the compound to a subject to treat a bacterial infection, including infections caused by Mycobacterium tuberculosis, with the possibility of inhibiting a PASTA kinase such as PknB during treatment.
Co-administration with β-lactam antibiotics for bacterial infection treatment
Co-administering the compound and an antibiotic, such as a beta-lactam antibiotic, to a subject to treat bacterial infections with synergistic effects, potentially reducing drug resistance and improving therapy.
The independent claims cover the chemical entities for selective bacterial kinase inhibition, therapeutic methods using these compounds alone or in combination with antibiotics, particularly emphasizing treatment of bacterial infections by targeting PASTA kinases like PknB for enhanced specificity and efficacy.
Stated Advantages
Improved specificity of kinase inhibitors by exploiting structural differences between human and bacterial PASTA kinases.
Enhanced inhibitor activity contributing to effective bacterial kinase inhibition.
Potential to provide new and effective treatment options for resistant Gram-positive pathogens, including Mycobacterium tuberculosis and MRSA.
Ability to synergize with β-lactam antibiotics, potentially lowering required doses and reducing the likelihood of resistance development.
Selective inhibition of Gram-positive bacteria without affecting Gram-negative flora, improving safety.
Documented Applications
Treatment of bacterial infections caused by drug-resistant Gram-positive bacteria, including Mycobacterium tuberculosis, Staphylococcus aureus (including MRSA), Listeria monocytogenes, Streptococcus pneumoniae, Nocardia, Corynebacteria, and Propionibacteria.
Use of compounds to inhibit protein kinase activity, especially PASTA kinases like PknB, in subjects.
Co-therapy involving co-administration of the compounds with β-lactam antibiotics to treat bacterial infections effectively.
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