Intrinsic and Acquired Resistance in Enterococcus
Enterococcus is a genus of bacteria notable for its resilience and ability to resist many antibiotics. This resistance is categorized into two main types: intrinsic and acquired. Intrinsic resistance is a natural characteristic of the species, meaning the bacteria possess inherent mechanisms that prevent an antibiotic from being effective. In the case of bacitracin, enterococci have always displayed high intrinsic resistance. This means that even before widespread antibiotic use, these bacteria were less susceptible to bacitracin compared to other gram-positive bacteria like Staphylococcus aureus or Streptococcus pyogenes. This inherent property is a key reason bacitracin is not a clinically viable option for treating enterococcal infections.
On top of this intrinsic resistance, enterococci have demonstrated a remarkable ability to acquire additional resistance over time, often through the horizontal transfer of genetic material. For bacitracin specifically, high-level acquired resistance has been documented in species like E. faecalis. This resistance is frequently mediated by a specific gene locus, known as the bcrABDR operon, which is carried on a transferable plasmid. The spread of these mobile genetic elements through conjugative transfer further complicates the clinical picture, potentially transferring resistance to other bacteria, including vancomycin-resistant strains. The selective pressure from high-level bacitracin use in agricultural settings, such as poultry farming, has contributed to the prevalence of these resistant strains.
The Mechanism of Action of Bacitracin and the Basis of Resistance
To understand why Enterococcus is resistant, one must first grasp how bacitracin works. Bacitracin is a polypeptide antibiotic that inhibits bacterial cell wall synthesis. Its primary target is undecaprenyl pyrophosphate (also known as bactoprenol pyrophosphate), a lipid carrier molecule responsible for transporting peptidoglycan precursors across the bacterial cytoplasmic membrane to construct the cell wall. Bacitracin works by binding to this molecule and preventing its dephosphorylation, effectively blocking its recycling and halting cell wall construction. This mechanism is highly effective against many gram-positive bacteria, which rely heavily on this process for survival.
Enterococcus has evolved multiple strategies to evade this inhibitory action. The most well-documented mechanism for high-level resistance is the expression of an ATP-binding cassette (ABC) transporter system, encoded by the bcrABDR operon. This transporter functions as an efflux pump, actively removing bacitracin from the inside of the bacterial cell before it can reach its target. The expression of this pump is controlled by a regulatory protein, BcrR, which senses the presence of bacitracin and triggers the pump's production. Other resistance mechanisms have also been identified, including networks that regulate multiple antimicrobial peptides, such as the SapRS/RapAB system, which also affects resistance to other agents like daptomycin.
Factors contributing to bacitracin resistance in Enterococcus
- Intrinsic Resistance: A baseline level of resistance inherent to the Enterococcus genus.
- Efflux Pumps: Active transport systems, like the
bcrABDRoperon, that pump bacitracin out of the cell. - Regulatory Proteins: Sensor proteins, such as BcrR, that regulate the expression of resistance genes in response to bacitracin.
- Mobile Genetic Elements: Resistance genes located on plasmids that can be transferred between different bacteria.
- Cross-Resistance Pathways: Regulatory networks that mediate resistance to multiple antibiotics, including bacitracin and daptomycin.
Comparison of Enterococcal Resistance Mechanisms
| Feature | Intrinsic Resistance | Acquired High-Level Resistance |
|---|---|---|
| Mechanism | Expression of low-affinity penicillin-binding proteins and other inherent factors; some tolerance. | Active efflux via ABC transporters (e.g., bcrABDR) and modified regulatory pathways. |
| Genetic Basis | Genetically encoded on the chromosome, present in most members of the species. | Often carried on mobile genetic elements, such as plasmids, and transferable between bacteria. |
| Expression | Constitutively expressed as a normal function of the bacterial cell. | Can be inducible, with expression levels increasing in the presence of the antibiotic, regulated by proteins like BcrR. |
| Clinical Implications | Makes bacitracin ineffective for treating enterococcal infections. | High-level resistance can be transferred to other strains, including vancomycin-resistant enterococci (VRE), hindering potential alternative therapies. |
Clinical Implications and Alternative Treatments
Given the intrinsic and acquired resistance of Enterococcus to bacitracin, the antibiotic is not used clinically for systemic enterococcal infections. While a 1999 study explored the use of oral bacitracin with doxycycline for eliminating intestinal carriage of vancomycin-resistant E. faecium (VRE), it was found to be ineffective in achieving long-term eradication beyond the two-week treatment period. This demonstrates the clinical futility of using bacitracin against this resilient pathogen, even in targeted scenarios.
The widespread resistance of Enterococcus to multiple antibiotics, including the rise of VRE, has pushed the need for alternative treatment strategies. Clinicians must rely on other agents and synergistic combinations to treat serious infections caused by these bacteria. Some of these alternatives include newer agents like linezolid and daptomycin, although resistance to these has also emerged. In cases of high-level resistance, combination therapies involving a cell wall-active agent (like ampicillin for susceptible strains) and an aminoglycoside may be used to achieve a bactericidal effect. The continuous evolution of resistance in enterococci underscores the ongoing challenge for modern medicine in finding effective and reliable treatments. More information on enterococcal adaptability can be found in a relevant review: The Enterococcus: a Model of Adaptability to Its Environment.
Conclusion
In summary, the question, 'Is Enterococcus sensitive to bacitracin?', can be answered with a definitive 'no'. The bacteria's high intrinsic resistance, combined with the ability to acquire and transfer additional resistance genes via mobile elements like plasmids, renders bacitracin ineffective for therapeutic use against enterococcal infections. The primary mechanism of this resistance involves a sophisticated efflux pump system that actively removes the antibiotic from the cell, preventing it from interfering with cell wall synthesis. These pharmacological realities are critical for healthcare providers when choosing appropriate treatments for enterococcal infections, especially given the rising prevalence of multidrug-resistant strains like VRE. The resilience and adaptability of Enterococcus highlight the constant need for new antimicrobial strategies.
