The Growing Challenge of Macrolide Resistance
Macrolide antibiotics, such as erythromycin and azithromycin, are critical for treating various bacterial infections, especially in patients with penicillin allergies [1.2.2]. They function by binding to the bacterial ribosome's nascent peptide exit tunnel, disrupting protein synthesis [1.6.2]. However, their widespread use has fueled the rise of resistant bacteria, compromising their effectiveness. This resistance is not caused by a single factor but by several complex biochemical mechanisms, primarily driven by specific bacterial enzymes. Understanding these enzymes is crucial for developing new therapeutic strategies.
Primary Mechanism: Target-Site Modification by Erm Methyltransferases
The most prevalent and clinically significant mechanism of macrolide resistance is the modification of the antibiotic's target site on the bacterial ribosome [1.4.1, 1.4.2]. This modification is catalyzed by a family of enzymes called Erm (erythromycin ribosome methylase) methyltransferases [1.3.4].
These enzymes, encoded by various erm genes, add one or two methyl groups to a specific adenine nucleotide (A2058) in the 23S rRNA of the large ribosomal subunit [1.3.3, 1.3.6]. This methylation alters the conformation of the ribosome, which dramatically reduces the binding affinity of macrolide antibiotics [1.3.4]. Because lincosamides and streptogramin B antibiotics share an overlapping binding site, this enzymatic modification often confers cross-resistance to all three drug classes, a phenotype known as MLSB resistance [1.4.1].
The expression of erm genes can be either constitutive (always on) or inducible (activated in the presence of the antibiotic) [1.2.5]. Inducible resistance is a clever survival mechanism for bacteria, as the continuous production of Erm enzymes can reduce the cell's overall fitness [1.3.7].
Secondary Enzymatic Mechanisms: Drug Inactivation
Beyond altering the drug's target, bacteria have evolved enzymes that directly attack and inactivate the macrolide antibiotic itself. Two main classes of enzymes are responsible for this type of resistance [1.2.2, 1.6.6].
Macrolide Phosphotransferases (Mph)
Encoded by mph genes, these enzymes inactivate macrolides by adding a phosphate group to the 2'-hydroxyl group of the antibiotic's desosamine sugar [1.6.4, 1.4.3]. This phosphorylation prevents the drug from effectively binding to the ribosome [1.2.7]. Mph enzymes are widespread and found in both Gram-positive and Gram-negative bacteria, often located on mobile genetic elements that facilitate their spread [1.6.4]. Different Mph enzymes have varying substrate specificities; for instance, MphA primarily acts on 14- and 15-membered macrolides, while MphB can also modify 16-membered macrolides [1.6.4].
Erythromycin Esterases (Ere)
Encoded by ere genes, these enzymes hydrolyze the macrolactone ring, the core structure of macrolide antibiotics [1.2.1, 1.2.2]. This cleavage linearizes the drug, rendering it inactive because it can no longer bind to its ribosomal target [1.2.2]. The two most clinically significant types are EreA and EreB [1.2.5]. EreA has a more limited substrate range compared to EreB, which can confer resistance to most 14- and 15-membered macrolides [1.2.5]. Like other resistance determinants, ere genes are often found on plasmids, contributing to their dissemination among bacterial populations [1.2.5].
Other Resistance Mechanisms
While enzymatic modification is a primary driver, another significant mechanism is antibiotic efflux. This process is mediated by protein pumps embedded in the bacterial cell membrane that actively expel macrolides from the cell, preventing them from reaching their ribosomal target [1.4.1]. The most common efflux systems are encoded by mef (macrolide efflux) genes, which create a low-to-moderate level of resistance known as the M-phenotype. This phenotype is specific to 14- and 15-membered macrolides [1.5.1, 1.8.4].
Comparison of Resistance Mechanisms
| Mechanism | Key Genes | Enzyme/Protein | Mode of Action | Resistance Level & Spectrum |
|---|---|---|---|---|
| Target Modification | erm | Erm Methyltransferase | Methylates 23S rRNA, preventing drug binding. | High-level; MLSB phenotype (macrolides, lincosamides, streptogramins B) [1.4.1, 1.7.2]. |
| Drug Inactivation | mph | Macrolide Phosphotransferase | Phosphorylates the antibiotic, preventing ribosomal binding. | Variable; depends on the specific Mph enzyme [1.6.4, 1.4.3]. |
| Drug Inactivation | ere | Erythromycin Esterase | Hydrolyzes the antibiotic's lactone ring. | Affects 14- and 15-membered macrolides; not 16-membered ones [1.2.5]. |
| Antibiotic Efflux | mef | Mef Efflux Pump | Actively pumps the antibiotic out of the bacterial cell. | Low to moderate; M-phenotype (14- and 15-membered macrolides only) [1.5.1, 1.7.4]. |
Conclusion
While several enzymes contribute to macrolide resistance, the Erm methyltransferases are the most widespread and clinically important cause [1.4.1, 1.8.4]. These enzymes alter the antibiotic's ribosomal target, conferring high-level resistance. Additionally, drug-inactivating enzymes like macrolide phosphotransferases (mph) and erythromycin esterases (ere), along with efflux pumps (mef), form a multi-pronged defense for bacteria against this vital class of antibiotics. The prevalence of these resistance genes, often on mobile genetic elements, highlights the ongoing challenge of antibiotic resistance in clinical settings and the urgent need for continued surveillance and development of novel antimicrobial agents.
For more in-depth information, you can refer to the National Center for Biotechnology Information (NCBI): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351036/
