For Students : Can Bacteria Become Resistant to Bacteriophages Like They Do with Antibiotics?

Can Bacteria Become Resistant to Bacteriophages Like They Do with Antibiotics?

Introduction

Bacteriophages (phages)—viruses that infect and kill bacteria—have gained renewed attention as potential alternatives or complements to antibiotics, particularly in the context of rising antimicrobial resistance. Phage therapy, long used in parts of Eastern Europe, is being reconsidered globally as a solution to drug-resistant infections. However, a crucial question arises: can bacteria become resistant to phages in the same way they become resistant to antibiotics? The short answer is yes—bacteria can evolve resistance to bacteriophages, but the underlying mechanisms, evolutionary dynamics, and clinical consequences are distinct from those associated with antibiotic resistance.

This article explores the diverse strategies bacteria employ to resist phage infection, the evolutionary implications of phage-bacteria interactions, and how this resistance differs from antibiotic resistance.

Mechanisms of Phage Resistance in Bacteria

1. Prevention of Phage Adsorption

The initial step of phage infection involves binding to specific receptors on the bacterial surface. Bacteria can evade this step by:

• Altering or masking surface receptors (e.g., via point mutations or phase variation);

• Producing extracellular matrix materials (e.g., capsules or biofilms) that physically block phage access;

• Downregulating receptor expression under selective pressure.

This mechanism is conceptually similar to how bacteria can resist antibiotics by reducing permeability or modifying target structures.

Example: Escherichia coli can mutate outer membrane proteins like LamB to resist λ-phage adsorption.

2. Superinfection Exclusion Systems

Some bacteria express superinfection exclusion (Sie) proteins that prevent DNA from entering the cytoplasm after phage binding. These proteins often come from prophages integrated into the bacterial genome and act as a form of “preemptive immunity” against similar invading phages.

Analogy: This is akin to a locked door that prevents a burglar from entering, even if they’ve picked the lock.

3. Restriction–Modification (R-M) Systems

R-M systems are a classic defense mechanism involving two enzymes:

• Restriction enzymes that cut foreign DNA at specific sequences;

• Modification enzymes (methyltransferases) that methylate the host’s own DNA to prevent self-destruction.

These systems can degrade invading phage genomes before they have a chance to replicate.

Parallel with antibiotics: This resembles enzymatic degradation of antibiotics (e.g., β-lactamases), though the target is genetic rather than chemical.

4. CRISPR–Cas Adaptive Immunity

Perhaps the most sophisticated bacterial defense against phages is the CRISPR–Cas system, an adaptive immune strategy where bacteria “remember” previous phage infections by integrating short sequences (spacers) from viral genomes into their own genome.

Upon reinfection, these spacers guide Cas proteins to recognize and cleave matching phage DNA.

Source: Labrie et al. (2010); Barrangou et al. (2007, Science); Horvath & Barrangou (2010, Science)

5. Abortive Infection Systems (Abi)

In a form of bacterial altruism, some cells employ abortive infection systems, which trigger cell death upon phage infection. This prevents phage replication and limits the spread of infection in the population.

Biological analogy: This is comparable to apoptosis in multicellular organisms—sacrificing the individual for the greater good.

Illustration : Evolutionary Dynamics between Phages and Bacteria as a Possible Approach for Designing Effective Phage Therapies against Antibiotic-Resistant Bacteria, https://www.mdpi.com/2079-6382/11/7/915

Phage Resistance vs. Antibiotic Resistance

While phage resistance and antibiotic resistance both involve evolutionary adaptations that reduce susceptibility, there are key differences:

Feature	Phage Resistance	Antibiotic Resistance
Mechanism	Physical, enzymatic, or immune-based	Enzymatic degradation, target alteration
Target Specificity	High specificity (often strain-specific)	Broader spectrum (antibiotics can hit multiple species)
Evolutionary Cost	Often high (e.g., loss of virulence or fitness)	Variable
Reversibility	Resistance can be lost when phage pressure is removed	Often more stable
Co-evolution	Phage-bacteria co-evolve dynamically	Antibiotics do not evolve

Importantly, while antibiotic resistance tends to accumulate and spread horizontally (via plasmids), phage resistance can be more localized and transient, depending on environmental and evolutionary pressures.

Implications for Phage Therapy

The ability of bacteria to develop phage resistance is a real concern, but it does not undermine the long-term viability of phage therapy for several reasons:

1. Co-evolutionary arms race: Phages can evolve in response to bacterial resistance, potentially restoring infectivity.

2. Phage cocktails: Using multiple phages with different receptor targets can reduce the chances of resistance emerging.

3. Synergy with antibiotics: Phages and antibiotics can act synergistically, where resistance to one may sensitize bacteria to the other.

4. Fitness costs: Many resistance mechanisms (e.g., receptor loss) come with trade-offs, such as reduced virulence or metabolic efficiency.

Thus, while resistance is a factor to monitor, it can often be managed or exploited to therapeutic advantage.

Conclusion

Yes, bacteria can and do become resistant to bacteriophages, much like they develop resistance to antibiotics. However, the molecular strategies and ecological dynamics of phage resistance are more diverse and complex, involving both innate and adaptive immune-like systems. Unlike antibiotics, phages themselves are capable of evolution, enabling them to overcome resistance in many cases. With thoughtful therapeutic design—such as the use of phage cocktails and monitoring for resistance—phage therapy remains a promising and adaptable tool in the fight against bacterial infections.

References :

• Labrie, S.J., Samson, J.E., & Moineau, S. (2010). Bacteriophage resistance mechanisms. Nature Reviews Microbiology, 8, 317–327. https://doi.org/10.1038/nrmicro2315

• Barrangou, R., Fremaux, C., Deveau, H., Richards, M., Boyaval, P., Moineau, S., ... & Horvath, P. (2007). CRISPR provides acquired resistance against viruses in prokaryotes. Science, 315(5819), 1709–1712.

• Samson, J.E., Magadán, A.H., Sabri, M., & Moineau, S. (2013). Revenge of the phages: defeating bacterial defences. Nature Reviews Microbiology, 11, 675–687.

• Seed, K.D. (2015). Battling phages: How bacteria defend against viral attack. PLoS Pathogens, 11(6), e1004847.