Cyclic Boronate Beta-Lactamase Inhibitors for Resistant Bacteria
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Solution Overview
Problem
Current antibiotic treatments for Stenotrophomonas maltophilia and Pseudomonas infections are hindered by widespread resistance, particularly due to the production of β-lactamases, which render β-lactam antibiotics ineffective, necessitating the development of new β-lactamase inhibitor combinations to enhance treatment efficacy.
Innovation Solution
The use of cyclic boronate β-lactamase inhibitors in conjunction with β-lactam antibiotics to treat Stenotrophomonas maltophilia, tuberculosis, or Pseudomonas infections, aiming to overcome resistance by sensitizing bacteria to antibiotic treatment and potentiating the effects of β-lactam antibiotics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If β-lactam antibiotics are used to treat bacterial infections, then treatment effectiveness is improved, but bacterial resistance develops due to β-lactamase production
Solution Approach 1:
The patent introduces β-lactamase inhibitors as intermediary substances that mediate between the β-lactam antibiotic and the bacterial β-lactamase enzyme. These inhibitors bind to and inhibit the β-lactamase enzyme, preventing it from degrading the antibiotic, thereby restoring and enhancing the antibiotic's effectiveness against resistant bacteria.
Solution Approach 2:
The patent applies preliminary anti-action by administering β-lactamase inhibitors alongside or before β-lactam antibiotics to preemptively block the bacterial resistance mechanism. The inhibitors预先 (in advance) inhibit the β-lactamase enzyme, preventing it from inactivating the antibiotic before the antibiotic can exert its therapeutic effect.
2Reliability
If clavulanic acid is used as a β-lactamase inhibitor, then activity against Class A SBLs is improved, but spectrum of activity is limited and irreversible inhibition causes side effects
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of β-lactamase inhibitors to achieve reversible inhibition while maintaining or enhancing activity. The cyclic boronate compounds described in the patent represent a structural parameter change from traditional irreversible inhibitors like clavulanic acid, enabling tunable inhibition strength and broader spectrum activity including against MBLs.
Solution Approach 2:
The patent uses composite molecular structures combining cyclic boronate cores with various substituent groups (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99, R100) to create a series of compounds with tailored properties, combining the benefits of different structural features to achieve broad-spectrum activity and optimized pharmacological characteristics.
3Adaptability or versatility
If avibactam is used as a β-lactamase inhibitor, then broader spectrum activity is improved, but activity against MBL-producing bacteria is absent
Solution Approach 1:
The patent aims to create universal β-lactamase inhibitors with multi-functional activity against multiple β-lactamase classes including SBLs and MBLs. The cyclic boronate compounds are designed to interact with both serine and metallo-β-lactamases through different binding mechanisms, achieving broad-spectrum coverage that includes MBLs, which avibactam cannot inhibit.
4Object-affected harmful factors
If S. maltophilia produces multiple β-lactamases, then resistance to all β-lactams is improved, but combination therapy with appropriate inhibitors can restore susceptibility
Solution Approach 1:
The patent uses β-lactamase inhibitors as intermediary agents that specifically target and inhibit the β-lactamase enzymes produced by S. maltophilia. By blocking these enzymes, the inhibitors restore the susceptibility of S. maltophilia to β-lactam antibiotics, allowing combination therapy to overcome the resistance problem.
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 combination of cyclic boronate β-lactamase inhibitors with β-lactam antibiotics effectively counters bacterial resistance, enhancing the therapeutic efficacy against Stenotrophomonas maltophilia and Pseudomonas species by inhibiting β-lactamases and restoring the effectiveness of β-lactam antibiotics.
Implementation Method 1
β-lactamases are the most commonly encountered cause of resistance to β-lactam antibiotics... β-lactamases render β-lactams inactive through two steps that involve acylation and de-acylation, which ultimately results in hydrolysis of the β-lactam ring
Implementation Method 2
The potency of avibactam against Class A, C and some Class D SBLs is attributed in part to the stabilization of the carbamoyl complex due to formation of a stable acyl-enzyme complex due to interactions with polar residues present in the active site
Implementation Method 3
The effective treatment of many fatal bacterial infections is underpinned by the administration of a course of β-lactam antibiotics
Data Source
AI summary
The present invention relates to the use of certain β-lactamase inhibitors in conjunction with one or more ⊕-lactam antibiotics for the treatment of Strenotrophomonas maltophilia, tuberculosis or Pseudomonas species infections.