From the Guidelines
Enzymatic inactivation is a key mechanism of antimicrobial resistance, where bacteria produce enzymes that modify or destroy antibiotics, rendering them ineffective, as seen in the production of phosphotransferases in S. aureus, Escherichia coli, and Nocardia species, which can inactivate macrolides like erythromycin 1. This mechanism is a major concern in the treatment of infections, as it can lead to the development of resistant bacterial strains, making it challenging to select effective antibiotics. Some of the key enzymes involved in enzymatic inactivation include:
- Beta-lactamases, which hydrolyze the beta-lactam ring in penicillins, cephalosporins, and carbapenems
- Carbapenemases, such as KPC and NDM enzymes, which confer resistance to carbapenems like meropenem
- Aminoglycoside-modifying enzymes, which add chemical groups to antibiotics like gentamicin, preventing them from binding to bacterial ribosomes
- Chloramphenicol acetyltransferases, which neutralize chloramphenicol
- Macrolide esterases, which can inactivate erythromycin To combat enzymatic inactivation, clinicians often use beta-lactamase inhibitors, such as clavulanic acid in amoxicillin-clavulanate or avibactam in ceftazidime-avibactam, which bind to and inhibit these enzymes 1. Understanding the specific enzymatic resistance mechanism is crucial for selecting appropriate antibiotics, as some newer agents are designed to evade or withstand enzymatic attack. This mechanism explains why antibiotic susceptibility testing is essential before initiating treatment for serious infections, especially in healthcare settings where resistant organisms are prevalent 1. In addition, a comprehensive approach to infections, including the use of rapid testing strategies to identify specific carbapenemases, can help guide antibiotic therapy and improve patient outcomes 1. Overall, enzymatic inactivation is a significant mechanism of antimicrobial resistance, and understanding its role is critical for developing effective treatment strategies.
From the FDA Drug Label
Resistance to amoxicillin is mediated primarily through enzymes called beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive.
The mechanism of resistance to amoxicillin is through enzymatic inactivation by beta-lactamases, which break the beta-lactam ring of the antibiotic, making it ineffective against the bacteria. 2 3
From the Research
AMR Mechanism - Enzymatic Inactivation
- Enzymatic inactivation is a key mechanism of antibiotic resistance, where bacteria produce enzymes that degrade or modify antibiotics, rendering them ineffective 4.
- Beta-lactamase enzymes are a common example of this mechanism, where they hydrolyze the beta-lactam ring of beta-lactam antibiotics, leading to their inactivation 5, 6, 7, 8.
- To combat this resistance mechanism, beta-lactamase inhibitors are often combined with beta-lactam antibiotics to prevent enzymatic degradation 5, 6, 7, 8.
- Studies have shown that combinations such as piperacillin/tazobactam, cefoperazone/sulbactam, and ticarcillin/clavulanic acid exhibit broad-spectrum activity against Gram-positive and Gram-negative bacteria, including those producing beta-lactamases 5, 6, 7.
- The choice of combination agent depends on various factors, including the type and quantity of beta-lactamase produced by the target bacterium, as well as the pharmacokinetics of the inhibitor 6.
- Understanding the molecular mechanisms of resistance enzymes and their three-dimensional structure can help in developing new approaches to anti-infective therapy 4.