Cephem Compounds with Catechol Group for Beta-Lactamase Resistance
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Solution Overview
Problem
Current Cephem compounds exhibit limited potency against beta-lactamase producing Gram negative bacteria, particularly those producing Class B type metallo-beta-lactamase, and often show cross-resistance with existing Cephem and Carbapenem drugs, necessitating the development of compounds with enhanced antimicrobial activity and specificity.
Innovation Solution
The development of Cephem compounds featuring a cyclic quaternary ammonium group on the 3-position side chain with a catechol type substituent, a spacer moiety, an aminothiadiazol or aminothiazol ring on the 7-position side chain, and a carboxylic group on the oxime moiety, which do not exhibit cross-resistance with known Cephem or Carbapenem drugs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional Cephem compounds are used, then broad antimicrobial spectrum is achieved, but potency against beta-lactamase producing Gram negative bacteria is limited
Solution Approach 1:
The patent introduces a catechol group at the 3-position side chain of the Cephem backbone, creating a localized functional modification that specifically enhances activity against metallo-beta-lactamase producing Gram negative bacteria without compromising the broad spectrum activity against other bacteria
Solution Approach 2:
The invention combines the Cephem core structure with a catechol-containing side chain and specific substituent patterns (aminothiadiazol/aminothiazol rings, carboxylic groups) to create a composite molecular structure that simultaneously achieves broad spectrum activity and potent activity against beta-lactamase producing bacteria
2Reliability
If existing Cephem and Carbapenem drugs are used, then antimicrobial treatment is provided, but cross-resistance occurs in multi-drug resistant bacteria
Solution Approach 1:
The patent inverts the conventional approach by placing the catechol group (known for Fe3+ chelation) at the 3-position side chain rather than the typical 7-position, and by incorporating specific substituent patterns that are not found in existing Cephem or Carbapenem drugs, thereby achieving compounds that do not exhibit cross-resistance
3Reliability
If Cephem compounds with catechol group are used, then activity against Gram negative bacteria is enhanced, but specificity against Class B type metallo-beta-lactamase is insufficient
Solution Approach 1:
The patent optimizes specific molecular parameters including the type of substituent on the catechol group (chlorine, fluorine, or hydrogen), the presence of aminothiadiazol or aminothiazol rings, and the configuration of carboxylic groups to achieve high specificity against Class B type metallo-beta-lactamase while maintaining broad activity against Gram negative bacteria
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
These compounds demonstrate potent antimicrobial activity against a wide range of bacteria, including multi-drug resistant Gram negative bacteria, with high stability against beta-lactamase producing bacteria, minimal side effects, and effective bioavailability, making them suitable for various infectious diseases.
Implementation Method 1
The action thereof is that the catechol group forms a chelate with Fe 3+
Data Source
AI summary
The present invention provides Cephem compounds which have a wide antimicrobial spectrum and have potent antimicrobial activity against beta-lactamase producing Gram negative bacteria as follows: a compound of the formula: or its ester, a compound protected at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof.