Clarithromycin Inhibits Pneumolysin Production via Downregulation of
            <i>ply</i>
            Gene Transcription despite Autolysis Activation

Domon, Hisanori; Isono, Toshihito; Hiyoshi, Takumi; Tamura, Hikaru; Sasagawa, Karin; Maekawa, Tomoki; Hirayama, Satoru; Yanagihara, Katsunori; Terao, Yutaka

doi:10.1128/spectrum.00318-21

Cited by 12 publications

(18 citation statements)

References 57 publications

(80 reference statements)

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“…Since ClpC and UvrC do not contain signal sequences for extracellular secretion, we hypothesized that LytA‐mediated lysis would be responsible for the extracellular release of both proteins. In accordance with our previous study, 18 culture supernatants of wild‐type and Δ lytA 24 strains of S. pneumoniae D39 were collected over time, and ClpC and UvrC in the supernatants were detected by Western blotting (Figure 2a). Six hours after the start of incubation (end of the exponential growth phase), obvious bands of both proteins were detected in the culture supernatants of the wild‐type strain by peptide antisera (obtained by subcontracting to Eurofins Genomics, peptide sequence: [ClpC] NH 2 ‐C + VKADDSDLSPADKA‐COOH, [UvrC] NH 2 ‐C + EERVDYQTEGNHNE‐COOH).…”

Section: Figuresupporting

confidence: 78%

Pneumococcal proteins ClpC and UvrC as novel host plasminogen binding factors

Hirayama

Yasui

Sasagawa

et al. 2022

Microbiology and Immunology

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Two plasminogen binding proteins were identified from a mouse infected with Streptococcus pneumoniae. The pneumococcal proteins were annotated as ATP‐dependent Clp protease ATP‐binding subunit (ClpC) and excinuclease ABC subunit C (UvrC) using the isobaric tags for relative and absolute quantification (iTRAQ) method. Recombinants of both proteins showed significant binding to plasminogen and were found to promote plasminogen activation by tissue‐type plasminogen activator. In addition, ClpC and UvrC were LytA‐dependently released into the culture supernatant and bound to the bacterial surface. These results suggest that S. pneumoniae releases ClpC and UvrC by autolysis and recruits them to the bacterial surface, where they bind to plasminogen and promote its activation, contributing to extracellular matrix degradation and tissue invasion.

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Section: Figuresupporting

confidence: 78%

Pneumococcal proteins ClpC and UvrC as novel host plasminogen binding factors

Hirayama

Yasui

Sasagawa

et al. 2022

Microbiology and Immunology

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“…Wild‐type and lytA ‐negative mutant (Δ lytA ) [15] strains of S. pneumoniae D39 were used. These pneumococcal strains were cultured in THY (Todd‐Hewitt broth [Becton, Dickinson, Franklin Lakes, NJ, USA] supplemented with 0.5% yeast extract) broth at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Triosephosphate isomerase of Streptococcus pneumoniae is released extracellularly by autolysis and binds to host plasminogen to promote its activation

et al. 2022

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Recruitment of plasminogen is an important infection strategy of the human pathogen Streptococcus pneumoniae to invade host tissues. In Streptococcus aureus, triosephosphate isomerase (TPI) has been reported to bind plasminogen. In this study, the TPI of S. pneumoniae (TpiA) was identified through proteomic analysis of bronchoalveolar lavage fluid from a murine pneumococcal pneumonia model. The binding kinetics of recombinant pneumococcal TpiA with plasminogen were characterized using surface plasmon resonance (SPR, Biacore), ligand blot analyses, and enzyme‐linked immunosorbent assay. Enhanced plasminogen activation and subsequent degradation by plasmin were also shown. Release of TpiA into the culture medium was observed to be dependent on autolysin. These findings suggest that S. pneumoniae releases TpiA via autolysis, which then binds to plasminogen and promotes its activation, thereby contributing to tissue invasion via degradation of the extracellular matrix.

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“…Clarithromycin is a derivative of erythromycin and differs structurally in the substitution of an O-methyl group for the hydroxy group at position 6 of the lactone ring. Clarithromycin negatively regulates ply gene transcription and activates pneumococcal autolysis [ 121 ]. On the other hand, in animal models of pneumonia caused by multidrug-resistant S .…”

Section: Resultsmentioning

confidence: 99%

Pneumolysin as a target for new therapies against pneumococcal infections: A systematic review

et al. 2023

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Background This systematic review evaluates pneumolysin (PLY) as a target for new treatments against pneumococcal infections. Pneumolysin is one of the main virulence factors produced by all types of pneumococci. This toxin (53 kDa) is a highly conserved protein that binds to cholesterol in eukaryotic cells, forming pores that lead to cell destruction. Methods The databases consulted were MEDLINE, Web of Science, and Scopus. Articles were independently screened by title, abstract, and full text by two researchers, and using consensus to resolve any disagreements that occurred. Articles in other languages different from English, patents, cases report, notes, chapter books and reviews were excluded. Searches were restricted to the years 2000 to 2021. Methodological quality was evaluated using OHAT framework. Results Forty-one articles describing the effects of different molecules that inhibit PLY were reviewed. Briefly, the inhibitory molecules found were classified into three main groups: those exerting a direct effect by binding and/or blocking PLY, those acting indirectly by preventing its effects on host cells, and those whose mechanisms are unknown. Although many molecules are proposed as toxin blockers, only some of them, such as antibiotics, peptides, sterols, and statins, have the probability of being implemented as clinical treatment. In contrast, for other molecules, there are limited studies that demonstrate efficacy in animal models with sufficient reliability. Discussion Most of the studies reviewed has a good level of confidence. However, one of the limitations of this systematic review is the lack of homogeneity of the studies, what prevented to carry out a statistical comparison of the results or meta-analysis. Conclusion A panel of molecules blocking PLY activity are associated with the improvement of the inflammatory process triggered by the pneumococcal infection. Some molecules have already been used in humans for other purposes, so they could be safe for use in patients with pneumococcal infections. These patients might benefit from a second line treatment during the initial stages of the infection preventing acute respiratory distress syndrome and invasive pneumococcal diseases. Additional research using the presented set of compounds might further improve the clinical management of these patients.

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Clarithromycin Inhibits Pneumolysin Production via Downregulation of ply Gene Transcription despite Autolysis Activation

Abstract: Pneumolysin is a potent intracellular toxin possessing multiple functions that augment pneumococcal virulence. For over 10 years, sub-MICs of macrolides, including clarithromycin, have been recognized to decrease pneumolysin production and release from pneumococcal cells.

Cited by 12 publications

References 57 publications

Pneumococcal proteins ClpC and UvrC as novel host plasminogen binding factors

Pneumococcal proteins ClpC and UvrC as novel host plasminogen binding factors

Triosephosphate isomerase of Streptococcus pneumoniae is released extracellularly by autolysis and binds to host plasminogen to promote its activation

Pneumolysin as a target for new therapies against pneumococcal infections: A systematic review

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