Bacterial Genetics & Drug Resistance
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Bacterial Genetics & Drug Resistance — Key Facts for FMGE Core concept: Bacterial resistance spreads via genetic elements (plasmids, transposons, integrons) High-yield point: Horizontal gene transfer allows rapid spread of resistance across species ⚡ Exam tip: Questions frequently test knowledge of specific resistance mechanisms and their genetic basis
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Bacterial Genetics & Drug Resistance — FMGE Study Guide
Bacterial Genetic Structures
Chromosome
- Single, circular DNA molecule
- Contains essential genes for growth and reproduction
- Mutations occur spontaneously at low rate (10⁻⁶ to 10⁻⁸ per generation)
Plasmids
- Extrachromosomal, circular, double-stranded DNA
- Replicate independently of chromosome
- Can be transferred between bacteria (conjugation)
- Carry non-essential but advantageous genes (antibiotic resistance, virulence factors)
- R plasmids: Encode antibiotic resistance
- F plasmids: Fertility factors for conjugation
Transposons
- “Jumping genes” that move within and between DNA molecules
- Simple transposons: Carry only transposase gene
- Composite transposons: Carry additional genes (often antibiotic resistance) between insertion sequences
Integrons
- Capture and express gene cassettes (especially antibiotic resistance genes)
- Found on chromosomes and plasmids
- Key in spread of multiple drug resistance
Gene Transfer Methods
1. Transformation
- Bacteria take up free DNA from environment
- Requires competent state (natural competence in S. pneumoniae, B. subtilis, H. influenzae)
- Used in laboratory for genetic engineering
- Key point for FMGE: Griffith’s experiment with Streptococcus pneumoniae - transformation of non-virulent rough strain to virulent smooth strain
2. Transduction
- Transfer of bacterial DNA via bacteriophages (viruses that infect bacteria)
- Generalized transduction: Random bacterial DNA packaged in phage (P1 phage in E. coli)
- Specialized transduction: Specific bacterial genes near phage attachment site transferred (lambda phage with gal genes)
- Lederberg and Tatum discovered this phenomenon
3. Conjugation
- Direct cell-to-cell transfer via sex pilus (F pilus)
- Requires cell contact (surface mating)
- Transfer of F plasmid or Hfr (high frequency recombination) chromosome
- Hfr strains: F plasmid integrated into chromosome → transfers chromosomal DNA
- Interrupted mating determines gene order (mapping)
- Resistance transfer via R plasmids (most important clinically)
Comparison Table
| Method | Vector | DNA Type | Clinical Relevance |
|---|---|---|---|
| Transformation | Free DNA | Any | Natural competence in pathogens |
| Transduction | Bacteriophage | Random or specific | Phage therapy, lab tool |
| Conjugation | Sex pilus | Plasmids/chromosome | Main spread of antibiotic resistance |
Drug Resistance Mechanisms
Intrinsic Resistance
- Natural characteristics of species (Gram-negative outer membrane, absence of target)
- Pseudomonas aeruginosa inherently resistant to many antibiotics due to efflux pumps and low permeability
Acquired Resistance
1. Enzymatic Inactivation
- Beta-lactamases: Hydrolyze beta-lactam ring (plasmid-mediated TEM, SHV, CTX-M)
- Aminoglycoside-modifying enzymes: Acetyltransferases, phosphotransferases, nucleotidyltransferases
- Chloramphenicol acetyltransferase
2. Target Modification
- Altered PBPs: MRSA (mecA gene encodes altered PBP2a)
- Altered DNA gyrase: Quinolone resistance
- Altered ribosomal target: Macrolide resistance (erm genes methylate 23S rRNA)
3. Decreased Drug Accumulation
- Porin mutations: Decrease antibiotic entry (carbapenem resistance in Enterobacter)
- Efflux pumps: Remove antibiotics from cell (tetracycline resistance via tet pump)
4. Bypass of Target
- Alternative metabolic pathways: Sulfonamide resistance (folate synthesis bypass)
Plasmids and Multiple Drug Resistance
R Plasmids (Resistance Plasmids):
- Carry multiple resistance genes simultaneously
- Often have transposons allowing movement between plasmids
- Spread rapidly in bacterial populations
- Example: IncF plasmids carrying blaCTX-M in Klebsiella pneumoniae
Extended-Spectrum Beta-Lactamases (ESBLs):
- Plasmid-mediated
- Hydrolyze cephalosporins and aztreonam (NOT carbapenems or cephamycins)
- Inhibited by beta-lactamase inhibitors (clavulanate, tazobactam)
- Common in E. coli, Klebsiella, Proteus
Carbapenemase producers:
- KPC (Klebsiella pneumoniae carbapenemase) - plasmid mediated
- NDM (New Delhi metallo-beta-lactamase)
- OXA enzymes
- Difficult treatment: combination therapy, tigecycline, colistin
Mutations and Resistance
Chromosomal mutations:
- Spontaneous mutations in target genes
- Frequency: 10⁻⁶ to 10⁻⁸ per generation
- Selected by antibiotic pressure
- Important examples:
- Rifampicin resistance: rpoB gene mutation
- Isoniazid resistance: katG, inhA mutations (TB)
- Fluoroquinolone resistance: gyrA mutations
Mutant prevention:
- High dose therapy
- Combination therapy
- Ensure adequate tissue penetration
Clinical Implications
Prevention of resistance spread:
- Appropriate antibiotic selection
- Complete treatment courses
- Infection control measures
- Surveillance of resistant organisms
- Antibiotic stewardship programs
Multidrug-resistant organisms (MDRO):
- MRSA: Methicillin-resistant Staphylococcus aureus (mecA gene)
- VRE: Vancomycin-resistant Enterococcus (vanA, vanB genes)
- ESBL producers
- Carbapenem-resistant Enterobacteriaceae (CRE)
- Important for hospital infection control
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