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Gene & Protein in Disease Phage therapy for Mycobacterium infections

first-line TB drugs. Although MDR-TB can be treated material into the host cell, hijacks the cellular machinery to
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using second-line drugs, these medicines are often costly, replicate, and eventually causes the cell to burst, releasing
potentially toxic, and may lead to further drug resistance. new phages to infect other cells. This process results in
This results in very limited treatment options for patients. the destruction of the host cell. The rapid and efficient
When TB bacteria are resistant to even the most effective killing of bacterial cells by lytic phages makes them
second-line drugs, it becomes a public health crisis and a highly effective for treating bacterial infections. They are
significant threat to health security. Unfortunately, in 2022, particularly useful for controlling and eliminating bacterial
only around two in five people with MDR-TB had access pathogens, particularly in cases where antibiotic resistance
to treatment. 4 is a concern. In addition, because the lytic cycle results in
the destruction of the host cell, it can significantly reduce
TB requires a prolonged course of antibiotics for 9
effective treatment, typically lasting 6 – 9 months for the bacterial load, aiding in the resolution of infections.
drug-susceptible TB. The extended duration of treatment On the other hand, in the lysogenic cycle, the phage
increases the likelihood of resistance developing, as patients integrates its genetic material into the host cell’s genome,
may not adhere to the full course of antibiotics or may be becoming a prophage. The host cell continues to replicate
exposed to suboptimal drug levels, leading to the survival with the integrated prophage until conditions trigger the
of resistant strains. Patients with mycobacterial infections prophage to switch to the lytic cycle. In addition to the
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often have underlying health conditions or risk factors traditional two life cycles, bacteriophages also undergo a
that complicate treatment, such as HIV infection, diabetes, third cleavage cycle. Filamentous phages can persistently
and malnutrition. The presence of comorbidities can infect the host bacteria for an extended period, produce
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weaken the immune system and make individuals more offspring phages, and release them into the environment
susceptible to drug-resistant mycobacterial infections, by means of bacterial outer membrane secretion, which
further exacerbating the problem. In addition, mycobacteria, avoids the death of the host but leads to chronic infection
including Mycobacterium tuberculosis and non-tuberculous and deceleration of the growth of the host. 11
mycobacteria, have a lipid-rich cell wall containing a unique Recently, there has been a growing emphasis on
component called mycolic acids. The mycolic acid layer forms investigating the mechanisms of gene expression in
a waxy, hydrophobic layer that acts as a barrier to restrict the mycobacteriophages. Researchers have observed two
entry of antibiotics into the bacterial cell, thereby conferring distinct life cycles – virulent and temperate – across various
intrinsic resistance to certain antibiotics. 6 clusters. The life cycle of M. tuberculosis bacteriophages
The therapeutic use of bacteriophages, or phages, started is impacted by the expression of particular genes during
two decades before the first clinical use of antibiotic drugs. the early and late stages of gene transcription. Early gene
However, the emergence of broad-spectrum antibiotics in transcription begins approximately 30 min after insertion,
the 1940s quickly overshadowed and marginalized phage whereas late gene transcription commences 30 min after
therapeutics in many parts of the world. Despite facing infection and lasts for approximately 180 min, ultimately
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setbacks, phage therapy persevered and continued to be resulting in the lysis of the infected M. tuberculosis. Non-
utilized in the Soviet Union and Eastern Europe. To this structural genes are expressed in the initial stages of
day, countries such as Poland, Russia, and Georgia have transcription, whereas late gene expression is responsible
maintained their use of phage therapy, but it was not until for encoding viral particle structures, integration of
the global rise of multidrug-resistant (MDR) bacterial genomic sequences, and cleavage cassettes. Several virulent
infections that genuine interest in implementing phage mycobacteriophages (Table 1), such as L5, D29, StarStuff,
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therapy on a clinical scale emerged in Western Europe, the Kampy, and SWU1 in cluster A, 12-15 Giles in cluster Q,
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Americas, and other regions worldwide. 7 Fruitloop in cluster F, and multiple phages in cluster N,
are commonly utilized in various research studies. 18
2. The life cycle of mycobacteriophages
3. Advantages and limitations of
Based on variations in the interactions between mycobacteriophages therapy
bacteriophages and host bacteria, the life cycle of
bacteriophages can be categorized into the lytic cycle and Given the widespread challenge of antibiotic resistance,
lysogenic cycle, with the corresponding bacteriophages the importance of phage therapy has been reasserted,
being referred to as virulent phages and temperate phages, demonstrating distinctive and effective results in specific
respectively. The lytic and lysogenic cycles are two distinct clinical instances of bacterial infections. Similar to most
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pathways that bacteriophages can follow when infecting other types of bacteriophages, mycobacteriophages share
bacterial cells. In the lytic cycle, the phage injects its genetic certain therapeutic benefits and drawbacks.

Volume 3 Issue 3 (2024) 2 doi: 10.36922/gpd.2935