Compositions and methods of use of antibacterial drug combinations
Inventors
Dantas, Gautam • Gonzales, Patrick • Forsberg, Kevin • Pesesky, Mitchell • Chang, Mayland • Mobashery, Shahriar
Assignees
Notre Dame Idea Center, University of • University of Notre Dame • Washington University in St Louis WUSTL
Publication Number
US-11559514-B2
Publication Date
2023-01-24
Expiration Date
2036-07-08
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Abstract
The present disclosure encompasses antibacterial compositions and methods of treating bacterial infections caused by resistant bacteria.
Core Innovation
The invention provides antibacterial compositions and associated treatment methods for infections caused by antibiotic-resistant bacteria, particularly those where resistance is due to a penicillin-binding protein 2a (PBP2a)-driven mechanism. The core composition includes: at least one carbapenem or other suitable β-lactam capable of binding the allosteric site of PBP2a; at least one β-lactamase inhibitor; and at least one β-lactam that binds the open configuration of the active site of PBP2a. The composition is specifically engineered to address antibiotic resistance exhibited by bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), by overcoming the mechanisms that usually render β-lactams ineffective.
The problem addressed is the growing threat of multidrug-resistant (MDR) pathogens, illustrated by the dramatic increase in MRSA infections that have become resistant to monotherapy with available antibiotics, including the β-lactam agent ceftaroline. Existing resistance mechanisms have limited the use of β-lactams, necessitating a new strategy for treating MDR pathogens and for repurposing existing antibiotics. The patent proposes a strategy of using a multi-component antibiotic composition targeting multiple sites within the bacterial cell wall synthesis system to both restore susceptibility and suppress resistance evolution.
According to the invention, the selected carbapenem (e.g., meropenem or imipenem) binds to the allosteric site of PBP2a, which opens the enzyme’s active site for subsequent inhibition by another β-lactam (such as piperacillin or amoxicillin) present in the composition. The β-lactamase inhibitor (such as tazobactam or clavulanate) protects these β-lactams from enzymatic degradation. This combined action achieves potent, synergistic, bactericidal activity against PBP2a-mediated resistant bacteria, while also suppressing the evolution of further resistance following treatment.
Claims Coverage
There is one independent claim in this patent, providing one main inventive feature.
Method for treating PBP2a-driven antibiotic-resistant bacterial infections using a specific multi-component β-lactam composition
The inventive feature is a method for treating an infection caused by an antibiotic resistant bacterium in a subject, where resistance is due to a penicillin-binding protein 2a (PBP2a)-driven mechanism. The method comprises administering an effective amount of a composition comprising: - At least one carbapenem or other β-lactam capable of binding the allosteric site of PBP2a; - At least one β-lactamase inhibitor; - At least one β-lactam that binds the open configuration of the active site of PBP2a. This method specifically targets infections with bacteria expressing PBP2a-based resistance, including but not limited to MRSA.
The independent claim provides protection for a treatment method employing a defined combination of a carbapenem (or suitable β-lactam) targeting the PBP2a allosteric site, a β-lactamase inhibitor, and a β-lactam targeting the open configuration of the PBP2a active site for PBP2a-mediated antibiotic resistance.
Stated Advantages
The composition suppresses the evolution of resistance to the antibiotic combination.
The combination acts synergistically and is bactericidal against bacteria comprising PBP2a, specifically MRSA.
The composition allows for the effective use of formerly inactive or obsolete β-lactam antibiotics against resistant bacteria.
Clinically relevant concentrations of the combination are below susceptibility breakpoints for each drug alone, enabling lower effective dosages.
Documented Applications
Treatment of infections caused by antibiotic-resistant bacteria with PBP2a-driven resistance mechanisms, including methicillin-resistant Staphylococcus aureus (MRSA).
Prevention or treatment of skin and soft tissue infections, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory tract infections, nosocomial pneumonia, bacteremia, meningitis, and surgical infections caused by relevant resistant bacteria.
Use in human, livestock animal, companion animal, laboratory animal, or zoological animal subjects suffering from or susceptible to such infections.
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