Bacitracin is a polypeptide antibiotic, often used topically, that disrupts bacterial cell wall synthesis by preventing the recycling of the lipid carrier undecaprenyl pyrophosphate (UPP). While potent against many susceptible Gram-positive bacteria, its efficacy is limited by a range of resistance mechanisms. The organisms resistant to bacitracin are diverse, encompassing both bacteria with inherent resistance and those that have acquired it over time.
Understanding Bacitracin's Mechanism
To appreciate why some bacteria are resistant, it's essential to understand bacitracin's mode of action. The antibiotic binds to UPP, a crucial molecule that transports cell wall precursors across the bacterial membrane. By sequestering UPP, bacitracin prevents its dephosphorylation and reuse, effectively blocking the assembly of the peptidoglycan layer and causing cell lysis.
Intrinsic Resistance: Inherited Immunity
Intrinsic resistance refers to a natural, chromosomally encoded resistance that is part of a bacterium's genetic makeup and does not arise from antibiotic exposure. This form of resistance is widespread and is primarily found in Gram-negative bacteria due to their fundamental structural differences.
Gram-Negative Outer Membrane
Most Gram-negative bacteria are intrinsically resistant to bacitracin. Unlike Gram-positive bacteria, they possess an outer membrane that acts as a formidable permeability barrier. This membrane, which lies outside the peptidoglycan layer, prevents the bacitracin molecule from reaching its target, the UPP, in the inner membrane. Classic examples of intrinsically resistant Gram-negative bacteria include:
- Escherichia coli
- Pseudomonas aeruginosa
- Xanthomonas campestris, which also produces exopolysaccharides that bind the antibiotic
Efflux Pumps
Even without the outer membrane barrier, some bacteria possess chromosomally encoded efflux pump systems that actively export the antibiotic out of the cell. This is a common intrinsic resistance mechanism, particularly in free-living bacteria that must tolerate natural toxins and antibiotics in their environment.
Acquired Resistance: Evolved Defenses
Acquired resistance develops when a previously susceptible organism gains resistance genes, often via horizontal gene transfer through plasmids or transposons. This process has led to resistance in some Gram-positive species that were once reliably susceptible to bacitracin.
ABC Transporters
One of the most documented acquired mechanisms involves ATP-binding cassette (ABC) transporters. These complex protein systems actively pump bacitracin out of the cell, protecting the UPP target. A notable example is the BcrABC transporter system, which has been identified in the following bacteria:
- Enterococcus faecalis: Studies have shown that high-level bacitracin resistance in this opportunistic pathogen is mediated by the plasmid-borne bcrRABD operon.
- Streptococcus mutans: The mbrA and mbrB genes, encoding a similar ABC transporter, are prominently induced by bacitracin exposure, leading to resistance in this caries-causing bacterium.
Overproduction of UPP Kinase
Some bacteria can overcome bacitracin's inhibitory effect by increasing the production of undecaprenol kinase. This enzyme increases the supply of UPP, flooding the cell with more target molecules than bacitracin can effectively sequester. By boosting the UPP pool, the bacteria can continue building their cell walls despite the presence of the antibiotic.
Exopolysaccharide Production
Certain bacteria, including some Gram-negative and Gram-positive species like S. mutans, develop resistance by altering the production of exopolysaccharides (EPS). Some of these EPS can bind to bacitracin, effectively sequestering it outside the cell and preventing it from reaching its target. S. mutans can form eDNA-dependent biofilms that promote horizontal gene transfer, further enhancing resistance.
Comparison of Bacitracin Susceptible vs. Resistant Organisms
| Feature | Susceptible Organism (S. pyogenes) | Resistant Organism (E. coli, E. faecalis) |
|---|---|---|
| Cell Wall | Thick peptidoglycan layer, lacks outer membrane. | Gram-negative: Outer membrane protects inner peptidoglycan layer. Gram-positive (E. faecalis): Acquired resistance allows bypass. |
| Bacitracin Access | Easily penetrates and reaches the UPP target. | Restricted by outer membrane (Gram-negative) or actively exported (acquired resistance). |
| Resistance Mechanism | Inherently sensitive to bacitracin's action. | Intrinsic: Outer membrane impermeability. Acquired: Efflux pumps (e.g., BcrABC), UPP kinase overproduction, or EPS production. |
| Bacitracin Test Result | Forms a distinct zone of inhibition around a 0.04-unit disk. | No zone of inhibition around the disk; bacterial growth is unaffected. |
| Clinical Implications | Effective target for topical bacitracin. | Topical bacitracin is ineffective; requires alternative antibiotics. |
Conclusion
Understanding what is resistant to bacitracin is crucial for appropriate treatment and controlling the spread of resistance. While many Gram-positive bacteria are susceptible, the inherent resistance of most Gram-negative species and the acquired resistance in others, like E. faecalis and S. mutans, highlights the limitations of bacitracin. These resistant organisms employ a variety of sophisticated mechanisms, from simple impermeability and efflux pumps to more complex metabolic adaptations. The continued evolution of resistance underscores the broader challenge of antibiotic stewardship and the need for new therapeutic strategies.
For more information on the molecular mechanisms of bacitracin resistance, consult reputable scientific sources such as the National Center for Biotechnology Information (NCBI).
