Īside from the unique mycobacterial outer membrane, the cytoplasmic membrane and peptidoglycan contribute to the integrity of the mycobacterial cell just as in both Gram-negative and Gram-positive bacteria. In response to this, mycobacteriophages are atypical in encoding a lipolytic enzyme, Lysin B, an esterase that hydrolyzes the linkage of the mycolic acids to the peptidoglycan-arabinogalactan complex,. The presence of the mycobacterial outer membrane is highly unusual for bacteria classified within the Gram-positive Actinomycetales. The most notable of these features is the mycobacterial outer membrane, a mycolic acid-rich double layer that is covalently attached to a layer of arabinogalactan, which is turn in covalently linked to the peptidoglycan that surrounds the cytoplasmic membrane. However, mycobacterial hosts have cell wall features that are distinct from most other bacterial hosts and can present additional challenges to phage lysis. Īs with all dsDNA-tailed bacteriophages, mycobacteriophages must ensure lysis of the host cell at the completion of the lytic cycle in order to release progeny phage particles. In spite of this great genetic diversity, all of these are tailed phages containing double-stranded DNA (dsDNA) morphologically classified in the order Caudovirales. In general, mycobacteriophage genomes are characteristically mosaic, with individual genes shared among otherwise unrelated genomes when compared at the amino acid sequence level. An additional eight genomes are singletons and have no close relatives. Genomes clustered together have nucleotide sequence similarity spanning more than 50% of their lengths and similar genome organizations genomes within a subcluster have a greater average nucleotide identity than between subclusters. These phages are highly genetically diverse and when grouped according to gross nucleotide sequence similarity they fall into 15 major clusters (A–O), many of which can be further divided into subclusters. The complete sequences of more than 220 mycobacteriophage genomes have been determined from phages that are known to infect a single common host, M. Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. Most contain three domains with a novel N-terminal predicted peptidase, a centrally located amidase, muramidase, or transglycosylase, and a C-terminal putative cell wall binding domain. We present here a bioinformatic dissection of these lysins and show that they are highly diverse and extensively modular, with an impressive number of domain organizations. Because mycobacterial peptidoglycan contains atypical features including 3→3 interpeptide linkages, it is not surprising that the mycobacteriophage endolysins also have non-canonical features. These include Lysin B proteins that cleave the linkage of mycolic acids to the arabinogalactan layer, chaperones required for endolysin delivery to peptidoglycan, holins that regulate lysis timing, and the endolysins (Lysin As) that hydrolyze peptidoglycan. Although little is known about how mycobacteriophages circumvent these barriers during the process of infection, destroying it for lysis at the end of their lytic cycles requires an unusual set of functions. The mycobacterial cell wall presents significant challenges to mycobacteriophages – viruses that infect mycobacterial hosts – because of its unusual structure containing a mycolic acid-rich mycobacterial outer membrane attached to an arabinogalactan layer that is in turn linked to the peptidoglycan.
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