Disease relevance of SP_1937

• Lipoteichoic acid: a specific inhibitor of autolysin activity in Pneumococcus [1].
• Furthermore, these compounds produced similar effects on other enzymes with different catalytic activities but that contained a similar choline binding domain; that is, autolysin (LytC) and the phage lytic enzyme (Cpl-1) [2].
• Subcellular localization of the major pneumococcal autolysin: a peculiar mechanism of secretion in Escherichia coli [3].
• Spontaneous autolysis in stationary phase also was negatively affected by capsule expression in an autolysin-dependent manner [4].
• The lytA-encoded autolysin (N-acetylmuramoyl-L-alanine amidase) of Streptococcus pneumoniae is believed to play an important role in the pathogenesis of pneumococcal infection and has been identified as a putative vaccine target [5]. A surface protein was recently identified in Streptococcus gordonii AtlS share similar structure and function as LytA [6].

High impact information on SP_1937

• Several pneumococcal proteins including pneumococcal surface proteins A and C, hyaluronate lyase, pneumolysin, autolysin, pneumococcal surface antigen A, choline binding protein A, and two neuraminidase enzymes are being investigated as potential vaccine or drug targets [7].
• Pneumococci carrying defined mutations in the genes encoding any one of at least three pneumococcal proteins (the toxin pneumolysin, the major pneumococcal autolysin, and pneumococcal surface protein A) have significantly reduced virulence [8].
• The first crystal structure of a choline binding domain, from the toxin-releasing enzyme pneumococcal major autolysin (LytA), reveals a novel solenoid fold consisting exclusively of beta-hairpins that stack to form a left-handed superhelix [9].
• Activation of an inactive form of autolysin by in vitro incubation with choline-containing cell walls is also inhibited by lipoteichoic acid [1].
• Choline-containing pneumococcal cell wals are sensitive to autolysin, whereas ethanolamine-containing walls are not [10].

Chemical compound and disease context of SP_1937

• DNA was extracted from the resultant erythromycin-resistant, autolysin-negative rough pneumococcus and used to transform S. pneumoniae D39, a virulent type 2 strain [11].
• Sucrose-independent adhesion of S. mutans in vitro has been shown to involve an ORF (ORF0317) encoding a homologue (39 %) to LytR, a regulator of autolysin activity in Bacillus subtilis [12].
• However, it was initially identified as a pneumococcus by a 16S RNA gene probe (Gen-Probe), optochin susceptibility and the presence of pneumolysin and autolysin [13].
• Using DNA extracts from a panel of EDTA bloods from patients with blood-culture-confirmed pneumococcal infection, the autolysin PCR had a sensitivity of 42.9%, which was similar to a previously reported TaqMan pneumolysin PCR (43.8%) run in parallel [14].

Biological context of SP_1937

• After methylation, the formerly autolysin-resistant walls could be quantitatively hydrolyzed by the pneumococcal autolysin [15].
• This phenotype was associated with the lack of surface expression of several CBPs, including the major autolysin LytA [16].
• Downregulation of the major autolysin in Streptococcus pneumoniae leads to penicillin tolerance, a feature that is characterized by the ability to survive but not grow in the presence of antibiotic [17].
• Voltammetric genosensors on streptavidin-modified screen-printed carbon electrodes (SPCEs) for the detection of virulence nucleic acid determinants of pneumolysin (ply) and autolysin (lytA) genes, exclusively present on the genome of the human pathogen Streptococcus pneumoniae, were described [18].
• These events paralleled the pattern of histology in the lung, with the severity of inflammation reduced with PLN-A and no inflammation or hematologic changes with AL-2 [19].

Anatomical context of SP_1937

• It is suggested that inhibition of cell wall synthesis by any means triggers bacterial autolytic enzymes by destabilizing the endogenous complex of an autolysin inhibitor (lipoteichoic acid) and autolytic enzyme [20].
• Roles of autolysin and pneumolysin in middle ear inflammation caused by a type 3 Streptococcus pneumoniae strain in the chinchilla otitis media model [21].
• It is suggested that the activator protein accelerates a normal process of transport (leakage) of autolysin molecules into the periplasmic space [22].
• The activity of these autolysin molecules from within would then unmask deoxyribonucleic acid binding sites located on the plasma membrane [22].

Associations of SP_1937 with chemical compounds

• Sensitivity of the cells to exogenous autolysin requires treatment with penicillin or other inhibitors of cell wall synthesis (e.g., D-cycloserine or fosfonomycin) since exogenous autolysin alone has no effect on bacterial growth [20].
• Ethanolamine-containing (autolysin-resistant) cell walls were methylated in vitro with methyl iodide [15].
• Several erythromycin-resistant transformants were obtained from two independent experiments, and none of these transformants produced autolysin [11].
• Cell walls isolated from pneumococci grown in the presence of clavulanate showed increased sensitivity to the hydrolytic action of purified pneumococcal autolysin in vitro [23].
• Breakdown of the cell wall appeared to be mediated mostly by the major pneumococcal autolysin, N-acetylmuramoyl-L-alanine amidase, because it was blocked by phosphorylcholine, a specific inhibitor of amidase, or by substitution of ethanolamine for choline in the cell wall [24].

Other interactions of SP_1937

• ClpC is required for the release of autolysin A and pneumolysin in serotype 2 S. pneumoniae strain D39 [25].
• Numerous virulence factors that include hyaluronidase, neuraminidase, iron-binding proteins, pneumolysin and autolysin then facilitate cytolysis of host cells and allow tissue invasion and bloodstream dissemination [26].

Analytical, diagnostic and therapeutic context of SP_1937

• On the basis of LCA models, sensitivity of autolysin PCR and pneumolysin PCR was 82% and 89%, respectively, but specificity was low, 38% and 27%, respectively [27].
• Southern blot analysis confirmed that the autolysin gene in these transformants had been interrupted by the plasmid-derived sequences [11].
• The lack of active autolysin in the mutant cells became apparent by impaired cell separation at the end of cell division and by resistance against stationary-phase and penicillin-induced lysis [28].
• Binding of pure pneumococcal autolysin to micelles of purified Forssman antigen could be demonstrated by mixing these components in vitro and analyzing them by sucrose density gradients and by agarose chromatography [29].
• Expression, crystallization and preliminary X-ray diffraction studies on the complete choline-binding domain of the major pneumococcal autolysin [30].

References