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Gene & Protein in Disease Phage therapy for Mycobacterium infections

classification systems are still evolving, and new clusters 5.2. Nucleoid-associated protein-Lsr2
and sub-clusters may emerge as further research and The conserved nucleoid-associated protein Lsr2, present
discoveries are made. The objective of these classification in mycobacteria and actinomycetes, is encoded by the Lsr2
systems is to enhance our comprehension of the diversity, gene. In M. tuberculosis, Lsr2 features two distinct domains:
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evolution, and role of mycobacteriophages. Investigations an N-terminal domain responsible for binding to DNA,
of mycobacteriophages have provided insights into viral with a preference for AT-rich sequences, and a C-terminal
diversity and evolution, revealing a substantial level of domain that facilitates the assembly of nucleoprotein
genetic diversity and a diverse gene repertoire of phages, filaments 52,53 (Figure 1). Similar to other bacterial nuclear-
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which encompasses numerous genes with unknown related proteins, Lsr2 polymerizes around DNA to organize
functions and many whose functions can be predicted but and compress bacterial chromatin and mediate DNA
are not typically present in phage genomes. The growing ligation. 54,55 The Lsr2 gene serves as a regulator of cell
number of sequenced genomes is conducive to a more wall synthesis in both M. tuberculosis and Mycobacteroides
profound understanding of mycobacteriophages. abscessus 56-58 as well as of virulence genes. In addition,
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it plays a role in antibiotic resistance. Dulberger et al.
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5. The regulatory effects of demonstrated the significant involvement of mycobacterial
mycobacteriophages-derived Lsr2 in numerous mycobacteriophage infections.
proteins/peptides Bacteriophages exhibit specific adsorption to locations
5.1. Antimicrobial peptide (AMP)-PK34 involved in the synthesis of the cell wall, whereas the Lsr2
protein undergoes recombination from chromosomal
Derived from the Mycobacterium D29 phage, PK34 is an DNA sites to the replication region of phage DNA, known
AMP that exhibits efficacy against M. tuberculosis. AMPs, as as ZOPR. Furthermore, they have shown that the absence
a category of biological antibacterial agents, operate through of Lsr2 has an impact on various mycobacteriophages,
distinct mechanisms of action compared to conventional resulting in inadequate establishment of ZOPR, resistance
antibacterial agents. AMPs are significant contenders for to phages, and disruption of viral spread at the population
eradicating drug-resistant bacteria due to their numerous level. The mechanisms underlying phage resistance
advantages, including their widespread presence, broad were further clarified in the context of their potential
spectrum of antibacterial activity, rapid sterilization, and application as therapeutic agents. In M. tuberculosis, the
absence of toxic side effects accumulation. Research presence of both Lsr2 domains is crucial for bacterial
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has indicated that AMPs have the potential to treat TB survival, thereby reducing the potential impact of Lsr2 loss
without the negative side effects commonly associated with as a resistance mechanism. In M. abscessus, Lsr2 is non-
chemotherapy drugs, such as liver injury, gastrointestinal essential, although its loss greatly reduces the virulence
symptoms, and allergic reactions. 47-49 Furthermore, of M. abscessus. M. abscessus Lsr2 has not been identified
AMPs do not confer resistance to M. tuberculosis. Wei in vitro or in vivo as a target for phage resistance, including
et al. conducted a screening of a minor polypeptide therapeutically useful phages, possibly reflecting a balance
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PK34 derived from M. tuberculosis bacteriophage D29, between phage sensitivity and pathogenicity.
which exhibits a specific affinity for trehalose dimycolate
(TDM), the predominant sugar ester present on the 5.3. The mechanism and function of trehalose
surface of M. tuberculosis. TDM is a core surface molecule polyphosphate (TPP)
of M. tuberculosis and represents a crucial target for Studies have demonstrated that bacteria are capable of
developing anti-TB medications. The ability of PK34 to acquiring resistance to bacteriophages. It is crucial to
eradicate M. tuberculosis and induce an anti-inflammatory
reaction has been well demonstrated. In vivo studies by
Wang et al. revealed that PK34 exhibited comparable
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efficacy to rifampicin in eliminating M. tuberculosis. The
peptide works by suppressing the release of inflammatory
cytokines by blocking the activation of mitogen-activated
protein kinase and protein kinase B while preserving a
specific threshold of inflammatory cytokines to uphold
normal immune function. Given these properties, PK34
is anticipated to serve as a supplementary medication for
managing M. tuberculosis infection or as a model for the
formulation of anti-TB medications. Figure 1. The mechanism of Lsr2

Volume 3 Issue 3 (2024) 5 doi: 10.36922/gpd.2935