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Mechanisms of bacterial resistance to antibiotics
1Pharmacy Department, New England Medical Center, Boston, Mass.
Abstract:
The three fundamental mechanisms of antimicrobial resistance are (1) enzymatic degradation of antibacterial drugs, (2) alteration of bacterial proteins that are antimicrobial targets, and (3) changes in membrane permeability to antibiotics. Antibiotic resistance can be either plasmid mediated or maintained on the bacterial chromosome. The most important mechanism of resistance to the penicillins and cephalosporins is antibiotic hydrolysis mediated by the bacterial enzyme beta-lactamase. The expression of chromosomal beta-lactamase can either be induced or stably depressed by exposure to beta-lactam drugs. Methods to overcome resistance to beta-lactam antibiotics include the development of new antibiotics that are stable to beta-lactamase attack and the coadministration of beta-lactamase inhibitors with beta-lactam drugs. Resistance to methicillin, which is stable to gram-positive beta-lactamase, occurs through the alteration of an antibiotic target protein, penicillin-binding protein 2. Production of antibiotic-modifying enzymes and synthesis of antibiotic-insensitive bacterial targets are the primary resistance mechanisms for the other classes of antibiotics, including trimethoprim, the sulfonamides, the aminoglycosides, chloramphenicol, and the quinolone drugs. Reduced antibiotic penetration is also a resistance mechanism for several classes of antibiotics, including the beta-lactam drugs, the aminoglycosides, chloramphenicol, and the quinolones.
Insights
Antimicrobial resistance arises from drug breakdown, target alteration, or reduced permeability. Strategies to combat this include developing new drugs and using enzyme inhibitors.
Area of Science:
- Microbiology
- Pharmacology
- Biochemistry
Background:
- Antimicrobial resistance (AMR) is a significant global health threat.
- Understanding the mechanisms of AMR is crucial for developing effective treatments.
- AMR can be mediated by plasmids or the bacterial chromosome.
Purpose of the Study:
- To elucidate the fundamental mechanisms of antimicrobial resistance.
- To explore resistance to beta-lactam antibiotics, including penicillins and cephalosporins.
- To review strategies for overcoming antibiotic resistance.
Main Methods:
- Review of established mechanisms of antimicrobial resistance.
- Analysis of beta-lactamase activity and its role in resistance.
- Examination of target modification and reduced permeability as resistance strategies.
Main Results:
- Key resistance mechanisms include enzymatic drug degradation, target alteration, and decreased membrane permeability.
- Beta-lactamase enzymes are critical for resistance to penicillins and cephalosporins.
- Resistance to methicillin involves alteration of penicillin-binding protein 2.
- Other antibiotics like trimethoprim, sulfonamides, aminoglycosides, chloramphenicol, and quinolones exhibit resistance via enzyme modification, target alteration, or reduced penetration.
Conclusions:
- Antimicrobial resistance is multifactorial, involving enzymatic, target-based, and permeability changes.
- Combating beta-lactam resistance requires novel antibiotics or beta-lactamase inhibitors.
- A comprehensive understanding of resistance mechanisms informs the development of new antimicrobial therapies.