From the Guidelines
Target modification is a primary antimicrobial resistance mechanism where bacteria alter the target structure, preventing antibiotic binding while maintaining cellular function. This mechanism occurs through mutations in target proteins, enzymatic modification, or acquisition of alternative proteins unaffected by the antibiotic 1. Examples include alterations in penicillin-binding proteins (PBPs) conferring resistance to beta-lactam antibiotics, mutations in DNA gyrase or topoisomerase IV reducing fluoroquinolone binding, and methylation of ribosomal RNA preventing macrolide binding 1. Key examples of target modification include:
- Methicillin-resistant Staphylococcus aureus (MRSA) acquiring the mecA gene, producing an alternative PBP (PBP2a) with low affinity for beta-lactams
- Vancomycin resistance in enterococci involving modification of peptidoglycan precursors to reduce vancomycin binding affinity Understanding these mechanisms is crucial for developing new antibiotics and implementing antibiotic stewardship practices to minimize resistant strain emergence 1. The rise in antimicrobial resistance is a national and international concern, with resistant bacterial strains potentially being transmitted to other individuals or establishing persisting reservoirs in the environment 1.
Some bacteria develop resistance to antimicrobials through target modification, while others may develop resistance through other mechanisms, such as enhanced drug efflux processes 1. The macrolides, such as erythromycin, clarithromycin, and azithromycin, inhibit RNA-dependent protein synthesis by bacteria, but resistance can occur through various mechanisms, including reduced permeability, altered target site, and enzymatic inactivation 1. Rising bacterial resistance rates to macrolides have been reported globally, with extensive macrolide use providing a strong selective pressure for the spread of macrolide resistance in pneumococci 1.
The encoding mechanism of bacterial resistance to an antibiotic's effect may be located on mobile genetic elements, such as plasmids or transposons, which can be inherited by future progeny or transferred to other strains or species 1. This highlights the importance of monitoring resistance mechanisms and implementing strategies to minimize the emergence of resistant strains. Therefore, understanding and addressing target modification is essential for effective antibiotic use and resistance management.
From the FDA Drug Label
In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. The linezolid resistance in these organisms was associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism.
The mechanism of resistance to linezolid is associated with point mutations in the 23S rRNA, specifically a substitution of thymine for guanine at position 2576. This is an example of target modification, where the target of the antibiotic (the 23S rRNA) is altered, reducing the effectiveness of the drug 2.
- Key points:
- Point mutations in the 23S rRNA are associated with linezolid resistance
- A specific point mutation (substitution of thymine for guanine at position 2576) has been identified in resistant organisms
- This mechanism of resistance is an example of target modification
From the Research
AMR Mechanism - Target Modification
- Target modification is a common mechanism of antimicrobial resistance, where the target site of the antibiotic is altered, reducing its effectiveness 3, 4.
- This can occur through spontaneous mutation of a bacterial gene or acquisition of resistance genes from other organisms through genetic exchange 4.
- Examples of target site modifications include mutations in RNA polymerase and DNA gyrase, resulting in resistance to rifamycins and quinolones, respectively 4.
- Enzymatic modification of antibiotic targets is also a prevalent resistance strategy, where the antibiotic target is subjected to chemical modification, such as methylation of rRNA, impairing the effectiveness of ribosome-targeting antibiotics 5.
- Understanding the mechanisms of target modification is crucial to combat resistance and develop novel agents that can overcome these resistance mechanisms 3, 6, 7.
- The prevalence of target modification as a resistance mechanism highlights the need for continued research into the development of new antibiotics and strategies to combat antimicrobial resistance 6, 7.