Zinc Chelating Compounds for Antibacterial Therapy
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Solution Overview
Problem
Current zinc chelators lack selectivity and safety, leading to toxicity issues when treating diseases associated with abnormal zinc levels, as they often penetrate eukaryotic cell membranes and affect normal cells, while existing antibacterial agents are ineffective against multidrug-resistant bacteria, particularly those producing metallo-β-lactamases.
Innovation Solution
Development of compounds with lipophilic zinc chelating moieties covalently bound to hydrophilic moieties, which are selective for Zn2+ ions and have a low log P value to minimize membrane penetration in eukaryotic cells, combined with antibacterial agents to target specific bacterial infections without harming host organisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If zinc chelators are used to treat diseases associated with abnormal zinc levels, then zinc homeostasis is regulated, but toxicity occurs due to penetration of eukaryotic cell membranes and effects on normal cells
Solution Approach 1:
The chelator molecule is designed with differentiated regions: a lipophilic zinc-chelating core for selective zinc binding and hydrophilic peripheral groups that prevent membrane penetration. This local quality differentiation allows the molecule to perform zinc regulation while avoiding toxicity to eukaryotic cells.
Solution Approach 2:
The invention creates a composite chelator structure combining lipophilic zinc-binding moieties (such as hydroxypyridinone groups) with hydrophilic moieties (such as sugar units or polyethylene glycol chains). This composite structure enables selective zinc chelation while the hydrophilic components reduce membrane permeability and cytotoxicity.
2Reliability
If existing antibacterial agents are used against multidrug-resistant bacteria, then bacterial infections are treated, but effectiveness is reduced due to metallo-β-lactamase-mediated resistance
Solution Approach 1:
The zinc-chelating compound acts as an intermediary agent that binds to zinc ions in metallo-β-lactamases, thereby inhibiting the enzyme's activity. This allows carbapenem antibiotics to remain effective by preventing the bacterial resistance mechanism from functioning.
Solution Approach 2:
The invention combines zinc-chelating properties with antibacterial activity in a single compound or formulation. The dual functionality allows simultaneous inhibition of metallo-β-lactamases and maintenance of carbapenem efficacy against resistant bacteria.
3Measurement precision
If lipophilic zinc chelating moieties are used for high zinc selectivity, then zinc chelation efficiency is improved, but membrane penetration in eukaryotic cells increases leading to toxicity
Solution Approach 1:
The chelator is segmented into distinct functional domains: a lipophilic zinc-chelating core that provides high zinc selectivity through specific coordination chemistry, and separate hydrophilic domains (such as sugar units or PEG chains) that reduce membrane permeability. This segmentation allows each part to perform its specific function without compromising the other.
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 effectively regulate zinc levels in biological systems with reduced toxicity to eukaryotic cells, demonstrating strong suppressive effects on metallo-β-lactamase-mediated resistance in bacteria, enhancing the efficacy of carbapenem antibiotics and reducing biofilm formation.
Implementation Method 1
lipophilic, zinc chelating moieties covalently bound to one or more hydrophilic moieties, wherein said zinc chelating moieties are selective for Zn2+ ions
Implementation Method 2
hydrophilic moieties are selected from non-peptidic hydrophilic monomeric, oligomeric and polymeric groups
Data Source
AI summary
The invention provides compounds for use in a method of treating and/or preventing a bacterial infection in a human or non-human mammal, said method comprising administration of said compound in combination with (either simultaneously, separately, or sequentially) a β-lactam antibiotic, wherein said compound has the general formula I:(wherein:Q is a lipophilic, zinc chelating moiety which is selective for Zn2+ ions and which comprises at least one, preferably two or more (e.g 2, 3 or 4), optionally substituted, unsaturated heterocyclic rings, e.g. 5 or 6-membered heterocyclic rings (such rings preferably include at least one heteroatom selected from N, S and O, preferably N); wherein any optional substituents may be selected from C1-6 alkyl, C1-6 alkoxy, halogen, nitro, cyano, amine, and substituted amine;each L, which may be the same or different, is a covalent bond or a linker;each W, which may be the same or different, is a non-peptidic hydrophilic group which comprises one or more hydroxy groups; andx is an integer from 1 to 3)or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.