Sulfonylurea Monocyclic β-Lactam Antibiotics Stable to β-Lactamases
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Solution Overview
Problem
Existing β-lactam antibiotics are ineffective against drug-resistant bacteria due to the emergence of enzymes like extended-spectrum β-lactamases (ESBLs), serine carbapenemases (KPCs), and metallo-β-lactamases (MBLs, leading to severe infections and health threats.
Innovation Solution
Development of sulfonylurea ring substituted monocyclic β-lactam antibiotics with enhanced permeability and broad-spectrum antibacterial activity, including compounds of formula (I) and their pharmaceutically acceptable salts, which are stable to metallo-β-lactamases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional β-lactam antibiotics (penicillin, cephalosporin, carbapenem) are used, then they can treat bacterial infections, but they become ineffective against drug-resistant bacteria due to enzyme degradation
Solution Approach 1:
The patent converts the harmful effect of β-lactamase enzymes into a benefit by designing monocyclic β-lactam antibiotics with specific structural features (aztreonam core structure) that are inherently resistant to degradation by these enzymes. The chemical structure modification creates a stable β-lactam ring that avoids recognition and hydrolysis by β-lactamases, thereby transforming the enzyme's harmful action into a non-issue.
Solution Approach 2:
The patent applies parameter changes by modifying the chemical structure of traditional β-lactam antibiotics to create monocyclic β-lactam compounds with specific substituent patterns at positions 2, 4, and 6 of the β-lactam ring. These structural parameter changes result in compounds that maintain antibacterial activity while achieving resistance to β-lactamase degradation.
2Reliability
If aztreonam is used to overcome MBL resistance, then stability to metallo-β-lactamases is achieved, but poor permeability and strong efflux reduce clinical effectiveness
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at particular positions of the monocyclic β-lactam ring structure. The substituents at positions 2, 4, and 6 are carefully selected to locally modify the molecule's properties - enhancing permeability through hydrophobic interactions while maintaining the core stability against MBLs. This localized modification approach allows independent optimization of different molecular properties.
Solution Approach 2:
The patent creates composite molecular structures by combining the stable monocyclic β-lactam core with various functional substituent groups. This composite approach integrates the beneficial properties of different molecular moieties: the core provides enzymatic stability while the substituents contribute to improved permeability and reduced efflux, achieving a synergistic effect.
3Reliability
If existing antibiotics are used, then they can treat infections, but narrow antibacterial spectrum limits treatment options against diverse pathogens
Solution Approach 1:
The patent achieves universality by designing a monocyclic β-lactam scaffold that inherently targets multiple types of bacteria through conserved peptidoglycan synthesis pathways. The aztreonam core structure provides broad-spectrum activity against gram-negative bacteria while the substituent modifications enable effective coverage against diverse pathogens including MBL-producing strains, making a single compound class applicable to multiple infection scenarios.
Data Source
AI summary
Sulfonylurea ring substituted monocyclic β-lactam antibiotics, and specifically relating to a compound represented by formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, and an application thereof in the preparation of medicaments for treating diseases related to bacterial infections.