Types of Resistance
Globally, bacterial resistance to antibiotics is divided into two major categories:
- Natural (intrinsic) resistance. This is a microorganism's genetically predetermined, natural insensitivity to a drug. It occurs when the bacterium completely lacks the "target" for a specific drug, or when the microbial envelope has such low permeability that the drug physically cannot reach the target. Prescribing an antibiotic in the presence of intrinsic resistance is completely useless. A classic example: Gram-negative bacteria are insensitive to vancomycin due to the structural features of their cell wall and enzymatic inactivation.
- Acquired resistance. This is the ability of individual strains to survive at drug concentrations that reliably destroy the main population of the same bacterial species. Based on the time of emergence, it can be:
- Primary — detected in some strains even before therapy begins (e.g., resistance of certain S. aureus strains to benzylpenicillin).
- Secondary — develops directly during the patient's treatment course.
Genetic Mechanisms of Development
Acquired resistance arises through two main pathways: via spontaneous mutations followed by natural selection of surviving clones, or through the acquisition of pre-existing genes from other bacteria.
- Chromosomal mutations (vertical transmission). Changes affect genes encoding target proteins or drug transport systems. The mutant gene is transmitted from the mother cell to daughter cells strictly during cell division.
- Horizontal gene transfer. This is the acquisition of foreign genetic material from other bacteria. This exact pathway leads to the emergence of dangerous nosocomial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).
Bacteria exchange DNA via three mechanisms:
- Conjugation — direct transfer of DNA (chromosomal or plasmid) via direct cell-to-cell contact.
- Transduction — gene transfer mediated by bacteriophages (bacterial viruses).
- Transformation — uptake of naked DNA from the extracellular environment by a bacterium.
Important: The vast majority of drug resistance cases are driven by the transfer of plasmids — extrachromosomal DNA molecules that carry specific resistance genes.
Biochemical Defense Mechanisms
Genetic alterations are executed at the molecular level. The bacterial cell employs several strategies to neutralize the threat:
- Target modification. The bacterium alters the structure of the protein or receptor that the drug is supposed to bind to. The drug simply stops "recognizing" its target.
- Enzymatic inactivation. The microbe produces specific enzymes that physically degrade the antibiotic molecule.
- Impaired drug uptake. The cell either reduces its wall permeability (preventing drug entry) or activates active efflux — pumping the drug out before it can take effect.
- Metabolic bypass ("shunt"). The bacterium develops an alternative metabolic pathway, surviving even when the primary pathway is blocked.
Distribution of Mechanisms by Drug Classes:
| Mechanism | Typical Antibiotic Classes |
|---|---|
| Vulnerable to all three main pathways | Beta-lactams, tetracyclines |
| Target modification | Beta-lactams, aminoglycosides, macrolides, fluoroquinolones, tetracyclines, clindamycin, rifampin, chloramphenicol, sulfonamides |
| Accumulation issues (efflux) | Fluoroquinolones (as well as beta-lactams and tetracyclines) |
| Enzymatic inactivation | Macrolides, chloramphenicol (as well as beta-lactams and tetracyclines) |