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Page 2 of 16 Varming et al. Microbiome Res Rep 2024;3:15 https://dx.doi.org/10.20517/mrr.2023.50

and Mor interact with each other. The structural basis of the interaction of φ13 CI and Mor was computationally
modeled and is similar to the interaction demonstrated experimentally between TP901-1 CI-NTD and Mor, likely
involving similar rearrangement of residue side chains during the formation of the complex. The study identifies
one CI residue, Glu69, which unusually interacts primarily through its aliphatic chain with an aromatic residue on
Mor after changing its conformation compared to the un-complexed structure. This and other residues at the
interface are suggested for investigation in future studies.

Keywords: Lysogeny switch, temperate phage, repressor, antirepressor, corepressor, pathogen, human adaptation

INTRODUCTION
Bacterial pathogens are major killers in view of rising antibiotic resistance. Staphylococcus aureus (S. aureus)
is a successful commensal found in about one-third of the healthy human population, but at the same time,
a dangerous opportunistic pathogen, with mortality ranging from 15%-50% in cases of S. aureus
[1]
bacteremia . One reason for the success of this “superbug” is the ease of acquisition of antibiotic
resistance . Methicillin-resistant S. aureus strains (MRSA) appeared within one year of first clinical use
[2,3]
and their global spread since then is a growing challenge. MRSA strains are commonly categorized as
hospital or healthcare-associated, community-associated, or livestock-associated, based on their major route
[4]
[5]
of transmission. Lysogenic conversion and transduction are two of the mechanisms by which phages
mediate the horizontal transfer of fitness genes between bacteria. In S. aureus, prophages are key
[6,7]
contributors to pathogenesis . S. aureus strains commonly carry between 1 and 4 prophages, and
importantly, most human strains carry a prophage belonging to the Sa3int family of bacteriophages . These
[8]
phages are characterized by encoding immune evasion factors that are specific to the human immune
[9]
system and thus they promote human colonization by the hosting strain . Interestingly, livestock strains of
S. aureus commonly do not carry Sa3int phages; however, recently, there have been observations of human
infections caused by livestock strains that have acquired phages of this family [10,11] . The adaptation of Sa3int
phages to livestock strains appears to have involved repeated integration and excision events that alter the
phage attP sequence needed for site-specific integration . Thus, Sa3int phages greatly influence the host
[12]
range of MRSA strains.

Bacteriophages are found in all known biological niches and environments that can accommodate bacteria,
[13]
which they outnumber by several folds . Lytic bacteriophages kill bacteria through lysis and are promising
for the treatment of antibiotic-resistant strains . In contrast, temperate bacteriophages can enter either a
[14]
lytic or a lysogenic lifecycle, where they, in addition to being lytic, can integrate their DNA into the bacterial
genome as prophages, and contribute to the virulence of the host. Bi-stable genetic switches (lysis-lysogeny
switches, hereon abbreviated as lysogeny switches) control whether the phage enters the lytic or lysogenic
cycle [4,15] .

[4,15]
In the Gram-negative Escherichia coli, the best-characterized lysogeny switch is that of phage λ , which is
also one of the best-studied models of gene regulations. The λ switch [Figure 1A] relies on several dimers of
the repressor CI (produced from the clear 1 - cI - gene) binding cooperatively to operator sites through their
DNA-binding N-terminal domain (CI-NTD). CI binds preferentially O O and O O in the O and O
R2
L2
L1
L
R1
R
operator sites, a process also involving DNA looping and long-range cooperativity, and thus blocks the lytic
cycle at P and expression of the repressor Cro at P . DNA damage induces the SOS response and promotes
R
L
the association of the bacterial protein RecA with single-stranded DNA . RecA filaments induce
[16]
autoproteolysis of CI by its LexA-like protease C-terminal domain (CTD) , leading to detachment from
[17]
DNA, and expression of lytic genes and the repressor Cro. Cro binds then preferentially to O , blocking the
R3
expression of CI and completing the switch to the lytic cycle. Despite some similar features, for example, a