Siderophore-dihydrofolate reductase inhibitor conjugate and application thereof
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Solution Overview
Problem
Existing siderophore-antibiotic conjugates face challenges in maintaining antibacterial activity due to limited or conservative action sites, and many antibiotics require detachment from link arms, while methotrexate, an effective anti-tumor drug, suffers from high toxicity to normal cells.
Innovation Solution
Development of a siderophore-dihydrofolate reductase inhibitor conjugate with a detachable linker, allowing targeted delivery of methotrexate through the bacterial iron transport system, enhancing antibacterial activity and reducing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If methotrexate is used as a standalone antibacterial agent, then it can inhibit dihydrofolate reductase in bacteria, but it exhibits high toxicity to human cells which hinders its antibacterial use
Solution Approach 1:
The patent segments the therapeutic function by separating the antibacterial action from the toxic effect. The siderophore component specifically targets bacterial iron uptake systems, while the methotrexate component provides the inhibitory function. This segmentation allows selective delivery of methotrexate to bacteria, improving antibacterial activity while reducing toxicity to human cells through targeted delivery.
Solution Approach 2:
The siderophore acts as an intermediary that mediates the delivery of methotrexate to bacteria. The siderophore-methotrexate conjugate utilizes the siderophore's natural affinity for bacterial iron transport systems to deliver methotrexate selectively to bacterial cells, thereby enhancing antibacterial efficacy while minimizing off-target toxicity to human cells.
2Device complexity
If conventional link arms are used in siderophore-antibiotic conjugates, then the conjugate structure is simplified, but the antibacterial activity is reduced due to limitations in transport efficiency and target delivery
Solution Approach 1:
The patent changes the chemical parameters of the link arm by incorporating a cleavable ester bond instead of a stable amide bond. This parameter change allows the link arm to be stable during transport but cleavable at the target site, thereby improving antibacterial activity through enhanced drug release while maintaining reasonable structural complexity.
Solution Approach 2:
The link arm is designed to be dynamic rather than static. The ester bond provides dynamic behavior by being stable in the bloodstream but cleavable by bacterial esterases at the target site. This dynamic property enables the conjugate to maintain structural integrity during transport while releasing the antibiotic at the bacterial target, thereby improving antibacterial activity.
3Adaptability or versatility
If siderophores are conjugated with antibiotics to enrich types of siderophore antibiotics, then the antibacterial spectrum is expanded, but the antibacterial activity is reduced due to the distance from the target after transport into the bacterial body
Solution Approach 1:
The patent extracts the siderophore from the final active form by designing a cleavable link arm. The siderophore is taken out as a delivery vehicle that releases the antibiotic at the target site. This extraction allows the conjugate to benefit from the siderophore's transport capabilities while eliminating the problem of the siderophore moiety interfering with target binding after transport into the bacterial body.
Solution Approach 2:
The siderophore performs preliminary action by facilitating transport of the conjugate into the bacterial cell. The cleavable link arm then releases the antibiotic at the appropriate location and time. This preliminary action by the siderophore followed by timely release ensures both expanded antibacterial spectrum through active transport and maintained antibacterial activity through proper timing and location of drug release.
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 conjugate significantly improves methotrexate's antibacterial activity against pathogens like Streptococcus pneumoniae while minimizing toxicity to human cells, offering a promising clinical development prospect.
Implementation Method 1
siderophores...connect a siderophore with...drugs...The affinity of ciprofloxacin for DNA gyrase may be weakened to a certain extent by modifying ciprofloxacin with a relatively large siderophore. The active transport of siderophores allows the drug to be enriched in the bacterial body
Data Source
AI summary
A conjugate provided. The conjugate is a compound represented by Formula (I), or the conjugate is a stereoisomer, tautomer, homologue, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound represented by Formula (I):where A is a linker, and B is a dihydrofolate reductase inhibitor; R1, R2, R3, R4, and R5 are independently selected from H or C1-6 alkyl; and n1, n2, and n3 are each an integer selected from 0 to 6.