Escherichia coli is a common bacterium found in the environment and the intestines of warm-blooded animals, including humans. While many strains are harmless, some can cause serious infections. Bacteriophages, often called phages, are viruses that specifically infect and replicate within bacteria. They represent a natural predator of bacteria, and their interaction often leads to a dynamic struggle where bacteria, including E. coli, can develop ways to resist phage infection.
The Battle Between E. coli and Phages
Bacteriophages are diverse viruses with varying shapes and genetic material (DNA or RNA). Lytic phages infect and destroy their bacterial hosts. Infection begins when a phage attaches to specific receptor sites on the bacterial cell surface, such as proteins or cell wall components. This attachment is often highly specific, meaning a phage may only infect certain bacterial strains.
Once attached, the phage injects its genetic material into the bacterial cytoplasm. The phage then takes over the bacterium’s machinery to replicate its genome and synthesize new proteins. New phage particles assemble inside the host cell. Finally, enzymes like endolysins degrade the bacterial cell wall, causing the cell to burst and release new phages to infect other bacteria. This continuous cycle of infection and lysis drives an evolutionary arms race, where phages evolve to infect more effectively, and bacteria evolve to resist.
How E. coli Becomes Resistant
E. coli has developed multiple strategies to defend against phage attacks, often targeting different stages of the phage life cycle. One defense blocks adsorption, the initial step of phage attachment. Bacteria achieve this by mutating or modifying cell surface receptors (e.g., outer membrane proteins, porins, LPS), hindering phage binding. For instance, LPS gene mutations can disrupt receptor synthesis, and capsule overproduction can mask receptors, preventing attachment.
Even if a phage successfully adsorbs, E. coli can prevent the injection of its genetic material. Some bacterial systems, often encoded by prophages, produce proteins that block phage genome injection into the cytoplasm.
Another defense is the restriction-modification (R-M) system. These systems consist of two enzymes: a restriction endonuclease (REase) and a DNA methyltransferase (MTase). The MTase modifies the bacterium’s own DNA with methyl groups, protecting it from cleavage. Conversely, the REase recognizes and cleaves foreign, unmodified DNA, like invading phage DNA, destroying it before replication.
The CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated) system provides E. coli with an adaptive immune response. When a bacterium survives phage infection, it captures small phage DNA fragments and integrates them as “spacers” into its CRISPR array. These spacers serve as a memory of past infections. Upon subsequent encounters, the CRISPR-Cas system transcribes these spacers into guide RNAs (crRNAs) that direct Cas proteins to cleave invading phage DNA, neutralizing the threat.
Finally, E. coli can employ abortive infection (Abi) systems, triggering programmed death of the infected cell. This sacrifices the infected cell to prevent phage replication and spread to the bacterial population. Abi systems interfere with phage propagation, protecting the community.
Consequences of Phage Resistance
Phage resistance in E. coli has implications for phage therapy, an alternative to antibiotics. Phage therapy uses phages to treat bacterial infections, offering a targeted approach. However, like antibiotic resistance, bacteria can evolve phage resistance, reducing treatment effectiveness.
Phage resistance mechanisms, such as modifications to cell surface receptors (e.g., K15 capsule or LPS), reduce phage binding and infection. This challenges clinicians and researchers combating antibiotic-resistant E. coli, as specific phage treatments can become ineffective if bacteria develop resistance. Studies confirm the difficulty of using phage therapy to reduce multidrug-resistant bacterial carriage.
Future Strategies Against Resistant E. coli
To address phage resistance, researchers are developing strategies to enhance phage-based treatments against E. coli. One approach uses phage cocktails, mixtures of multiple phages. By targeting different bacterial receptors or mechanisms, cocktails reduce the likelihood of simultaneous resistance to all phages. This broadens the host range and improves efficacy against diverse E. coli strains.
Phage engineering, genetically modifying phages, is another strategy. Researchers can engineer phages to expand their host range, infecting a wider variety of E. coli strains, including multidrug-resistant ones. This can involve replacing phage tail fiber genes or arming phages with CRISPR-Cas systems to eliminate E. coli strains. Such modifications aim to make phages more potent and less susceptible to bacterial defenses.
Understanding resistance evolution is an active research area, allowing scientists to predict and counter bacterial defenses. By studying how resistance develops, researchers can design more robust phage therapies. Combinatorial therapies, using phages with other treatments like antibiotics, are also being explored. This approach leverages both treatments, potentially reducing resistance development and enhancing antibacterial effects.