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Multiplicity of macrolide-lincosamide-streptogramin antibiotic resistance determinants
Abstract:
Bacteria can resist macrolide, lincosamide, and streptogramin (MLS) antibiotics enzymically by alteration of the target site or detoxification of the antibiotic. N6-dimethylation of adenine in 23 S ribosomal RNA confers resistance to M, L, and S B-type (MLSB) antibiotics. Investigation, by DNA annealing, of the relationship between the genes specifying this resistance mechanism from Streptococcus (groups A,B,D, and H, and pneumoniae), Staphylococcus aureus, Bacillus licheniformis, Bacteroides fragilis, Lactobacillus casei, and Streptomyces erythreus indicated substantial sequence diversity among the MLSB resistance (R) determinants. A minimum of four distinct classes of MLSB R determinants could be defined: classes A and B for the Gram-positive cocci (streptococci pmeumococci and staphylococci), class C for B. licheniformis, and class D for Bact. fragilis. These data do not support the hypothesis that the R determinants were acquired recently from a single common origin and suggest an easy exchange of genetic information among the Gram-positive cocci. The genetic classes do not correlate with differences in phenotypic expression or in regulation (inducibility or constitutivity) of resistance towards MLSB antibiotics. Inactivation of the drug confers resistance to M and/or L and/or S or SA or SB antibiotics and has been detected in strains of Streptococcus, Staph. aureus, Lactobacillus, C. perfringens, Streptomyces, and recently in the Gram-negative organism Escherichia coli. We have cloned and sequenced a DNA fragment conferring high level resistance (MIC greater than 2 g/l) to erythromycin by hydrolysis of the antibiotic. The distribution of this 'new' character in enterobacteria isolated from human faeces was studied by colony hybridization using an intragenic probe. The gene for the erythromycin esterase was detected in numerous strains of E. coli belonging to various biotypes, in Klebsiella pneumoniae, Enterobacter agglomerans, and in one 'coliform'. Moreover, our results indicated the existence of at least two classes of genes specifying resistance to erythromycin by inactivation of the antibiotic in enterobacteria.
Insights
Bacterial antibiotic resistance to MLSB drugs varies by genetic class, suggesting frequent gene exchange among Gram-positive bacteria. A new erythromycin resistance gene found in E. coli indicates diverse inactivation mechanisms.
Area of Science:
- Microbiology
- Molecular Biology
- Genetics
Background:
- Bacteria develop resistance to macrolide, lincosamide, and streptogramin (MLS) antibiotics through target modification or drug inactivation.
- N6-dimethylation of adenine in 23S ribosomal RNA is a key mechanism for resistance to MLSB antibiotics.
- Understanding the genetic diversity and origins of antibiotic resistance determinants is crucial for combating antimicrobial resistance.
Purpose of the Study:
- To investigate the genetic diversity of MLSB resistance determinants in various bacterial species.
- To explore the evolutionary origins of these resistance genes.
- To identify and characterize novel antibiotic inactivation mechanisms, specifically focusing on erythromycin resistance in enterobacteria.
Main Methods:
- DNA annealing techniques were used to analyze the relationship between MLSB resistance genes from diverse bacterial sources.
- Cloning and sequencing of a DNA fragment conferring high-level erythromycin resistance via hydrolysis.
- Colony hybridization with an intragenic probe to study the distribution of the erythromycin esterase gene in enterobacteria.
Main Results:
- Substantial sequence diversity was observed among MLSB resistance determinants, defining at least four distinct genetic classes (A, B, C, D) across Gram-positive bacteria and Bacteroides fragilis.
- The genetic diversity suggests frequent genetic exchange among Gram-positive cocci rather than recent acquisition from a single origin.
- A novel gene conferring high-level erythromycin resistance through antibiotic inactivation (esterase activity) was identified and found in numerous strains of E. coli and other enterobacteria, indicating at least two classes of such genes.
Conclusions:
- The genetic landscape of MLSB resistance determinants is diverse, with distinct classes in different bacterial groups.
- Evidence supports extensive genetic exchange of resistance mechanisms within Gram-positive bacteria.
- The discovery of a widespread erythromycin esterase gene in enterobacteria highlights a significant, previously underappreciated mechanism of antibiotic inactivation in Gram-negative pathogens.