Bicyclic Aryl Monobactam Compounds Overcome Gram-Negative Resistance
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Solution Overview
Problem
The emergence of antibiotic-resistant bacteria, particularly Gram-negative bacteria resistant to β-lactams, poses a significant medical threat due to the lack of effective treatments, with existing antibiotics like aztreonam showing limited efficacy against strains such as Pseudomonas and Acinetobacter, and the absence of inhibitors for metallo β-lactamases.
Innovation Solution
Development of bicyclic aryl monobactam compounds, which can be used alone or in combination with β-lactamase inhibitors like relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam, to effectively target and inhibit Gram-negative bacteria, including multidrug-resistant strains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing monobactam antibiotics like aztreonam are used, then treatment of Gram-negative bacterial infections is provided, but efficacy against resistant strains such as Pseudomonas and Acinetobacter is limited
Solution Approach 1:
The patent modifies the chemical structure of monobactam antibiotics by introducing bicyclic aryl groups and various substituents (halogens, alkyl groups, heterocycles) to change the pharmacological parameters of the compound. These structural parameter changes enhance binding affinity to penicillin-binding proteins and improve stability against β-lactamases, thereby expanding efficacy against resistant strains while maintaining the core monobactam mechanism of action
Solution Approach 2:
The invention creates composite antibiotic structures by combining the monobactam core with bicyclic aryl moieties and additional functional groups. This composite approach integrates multiple pharmacophores into a single molecule, providing both the β-lactamase resistance of monobactams and enhanced activity against difficult-to-treat Gram-negative bacteria through the added structural complexity
2Reliability
If β-lactamase inhibitors are developed for class A and C β-lactamases, then protection against these enzymes is achieved, but no inhibitors are available for class B metallo β-lactamases
Solution Approach 1:
The patent extracts and addresses the specific vulnerability to metallo-β-lactamases by designing monobactam derivatives with enhanced stability against these enzymes. The bicyclic aryl structure and specific substituent patterns provide steric and electronic protection that prevents class B β-lactamase access to the β-lactam ring, effectively extracting protection against this previously undefended enzyme class
Solution Approach 2:
The invented monobactam compounds achieve multi-functional protection by simultaneously resisting hydrolysis from multiple β-lactamase classes (A, B, C, and D) through their enhanced structural design. The molecules serve multiple protective functions: maintaining intrinsic monobactam resistance to metallo-β-lactamases while adding stability against serine β-lactamases through the bicyclic aryl framework and strategic substituent placement
Data Source
AI summary
The present invention relates to bicyclic aryl monobactam compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein A1, L, M, W, X, Y, Z, RX and Rz are as defined herein. The present invention also relates to compositions which comprise a bicyclic aryl monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of one or more beta-lactamase inhibitor compounds.