Site-Selective Glycopeptide Functionalization for Resistant Bacteria
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Solution Overview
Problem
There is a need for derivatives of glycopeptide antibiotics that are effective against vancomycin-susceptible or vancomycin-resistant enterococci and Staphylococcus aureus, as existing glycopeptide antibiotics have a narrow spectrum of action and are toxic, limiting their use to critically ill patients or those with β-lactam-resistant infections.
Innovation Solution
Site-selectively functionalized glycopeptide antibiotics, such as vancomycin, teicoplanin, and telavancin, with specific substitutions on their biaryl functionalities, are developed to enhance their activity against methicillin-susceptible and resistant Staphylococcus aureus, vancomycin-sensitive and resistant enterococci, and vancomycin-resistant Staphylococcus aureus, through halogenation and cross-coupling reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If glycopeptide antibiotics are used to treat infections, then they can inhibit peptidoglycan synthesis and kill bacteria, but they have narrow spectrum of action and are only effective against Gram-positive cocci
Solution Approach 1:
The patent applies local quality by introducing specific substitutions at defined positions (7d, 7f, 5e) on the biaryl functionality of glycopeptide antibiotics. These localized chemical modifications at specific sites on the molecule enhance the antibiotic's ability to bind to target bacteria while maintaining selectivity, thereby expanding the spectrum of action to include both vancomycin-susceptible and vancomycin-resistant strains without affecting the core mechanism of peptidoglycan inhibition
Solution Approach 2:
The patent employs parameter changes by systematically varying the chemical substituents at positions 7d, 7f, and 5e on the biaryl ring structure. By changing these chemical parameters (different halogen atoms, aromatic groups, or other substituents), the antibiotic's properties are optimized to overcome resistance mechanisms in various bacterial strains, expanding effectiveness from narrow Gram-positive coverage to broader activity including VRE and VRSA
2Reliability
If glycopeptide antibiotics are used to treat critically ill patients with β-lactam-resistant infections, then they can provide life-saving therapy, but their toxicity restricts their use
Solution Approach 1:
The patent applies local quality by making targeted substitutions at specific positions (7d, 7f, 5e) on the biaryl functionality while leaving the rest of the glycopeptide structure intact. This localized modification approach allows optimization of antibacterial activity and resistance profile without fundamentally altering the core structure responsible for therapeutic effectiveness, thereby potentially reducing toxicity while maintaining life-saving capabilities
3Reliability
If site-selective functionalization is performed on glycopeptide antibiotics through halogenation and cross-coupling reactions, then activity against resistant bacterial strains is enhanced, but the complexity of synthesis increases
Solution Approach 1:
The patent applies preliminary action by first introducing halogen atoms at positions 7d and 7f through halogenation reactions before performing cross-coupling reactions to install the desired substituents. This sequential approach, where the halogenation step is performed first to create reactive sites, simplifies the overall synthesis by establishing a clear reaction pathway and enabling selective functionalization at defined positions on the biaryl ring
Solution Approach 2:
The patent employs intermediaries by using halogen atoms as temporary placeholders or directing groups on the biaryl ring. These halogen substituents serve as intermediates that facilitate subsequent cross-coupling reactions with various aromatic or heteroaromatic groups. The halogen atoms mediate the transformation from the parent glycopeptide to the functionalized derivative, allowing controlled introduction of diverse substituents at positions 7d, 7f, and 5e
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The site-selectively functionalized glycopeptide antibiotics exhibit improved activity against targeted bacterial strains, providing a broader spectrum of action and potential therapeutic benefits for infections resistant to traditional glycopeptide antibiotics.
Implementation Method 1
The compounds can be functionalized after the cross-coupling reaction, e.g., halogenating already functionalized glycopeptide
Implementation Method 2
After halogenation, one of the halogenated sites can be further functionalized by a cross-coupling reaction
Implementation Method 3
The remaining halogens can be retained or removed by hydrogenation
Data Source
AI summary
Site-selective functionalized glycopeptide antibiotics, methods of making and using are described herein. The compounds exhibit improved activity against methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-sensitive S. aureus (VSE), vancomycin-resistant enterococci (VRE), or combinations thereof. The compounds can be administered as the neutral free acid or free base or can be administered as a pharmaceutically acceptable acid-addition or base-addition salt. The compounds can be formulated with one or more pharmaceutically acceptable excipients to prepare pharmaceutical compositions. The compounds can be administered by a variety of routes of administration including enteral, parenteral, topical, or transmucosal.