Combined Use of Bacteriophage K and a Novel Bacteriophage To Reduce Staphylococcus aureus Biofilm Formation

Alves, Diana R.; Gaudion, Alison; Bean, Jessica; Esteban, Patricia Perez; Arnot, Tom; Harper, David R.; Kot, Witold; Hansen, Lars H.; Enright, Mark C.; Jenkins, A. Toby A.

doi:10.1128/aem.01789-14

Cited by 155 publications

(147 citation statements)

References 64 publications

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“…Of particular relevance are the so-called methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) strains19. There are several studies demonstrating the successful utilization of bacteriophages against S. aureus 202122. For example, the lytic phage vB_SauM_phiIPLA-RODI (phiIPLA-RODI), belonging to the Myoviridae family, has been recently isolated from sewage samples and has shown promising results for the disruption of staphylococcal biofilms21.…”

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confidence: 99%

Low-level predation by lytic phage phiIPLA-RODI promotes biofilm formation and triggers the stringent response in Staphylococcus aureus

Fernández

González

Campelo

et al. 2017

Sci Rep

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An important lesson from the war on pathogenic bacteria has been the need to understand the physiological responses and evolution of natural microbial communities. Bacterial populations in the environment are generally forming biofilms subject to some level of phage predation. These multicellular communities are notoriously resistant to antimicrobials and, consequently, very difficult to eradicate. This has sparked the search for new therapeutic alternatives, including phage therapy. This study demonstrates that S. aureus biofilms formed in the presence of a non-lethal dose of phage phiIPLA-RODI exhibit a unique physiological state that could potentially benefit both the host and the predator. Thus, biofilms formed under phage pressure are thicker and have a greater DNA content. Also, the virus-infected biofilm displayed major transcriptional differences compared to an untreated control. Significantly, RNA-seq data revealed activation of the stringent response, which could slow down the advance of the bacteriophage within the biofilm. The end result would be an equilibrium that would help bacterial cells to withstand environmental challenges, while maintaining a reservoir of sensitive bacterial cells available to the phage upon reactivation of the dormant carrier population.

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confidence: 99%

Low-level predation by lytic phage phiIPLA-RODI promotes biofilm formation and triggers the stringent response in Staphylococcus aureus

Fernández

González

Campelo

et al. 2017

Sci Rep

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“…Bacteriophage phi812 from the genus Twort-like virus, subfamily Spounavirinae, can infect at least 95% of Staphylococcus aureus strains, including those strains resistant to antibiotics (2). Thus, phi812 has the potential to be used as antibacterial phage-therapy agent (3,4).…”

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Structure and genome release of Twort-like Myoviridae phage with a double-layered baseplate

Nováček

Šiborová

Benešík

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Bacteriophages from the family Myoviridae use double-layered contractile tails to infect bacteria. Contraction of the tail sheath enables the tail tube to penetrate through the bacterial cell wall and serve as a channel for the transport of the phage genome into the cytoplasm. However, the mechanisms controlling the tail contraction and genome release of phages with “double-layered” baseplates were unknown. We used cryo-electron microscopy to show that the binding of the Twort-like phage phi812 to the Staphylococcus aureus cell wall requires a 210° rotation of the heterohexameric receptor-binding and tripod protein complexes within its baseplate about an axis perpendicular to the sixfold axis of the tail. This rotation reorients the receptor-binding proteins to point away from the phage head, and also results in disruption of the interaction of the tripod proteins with the tail sheath, hence triggering its contraction. However, the tail sheath contraction of Myoviridae phages is not sufficient to induce genome ejection. We show that the end of the phi812 double-stranded DNA genome is bound to one protein subunit from a connector complex that also forms an interface between the phage head and tail. The tail sheath contraction induces conformational changes of the neck and connector that result in disruption of the DNA binding. The genome penetrates into the neck, but is stopped at a bottleneck before the tail tube. A subsequent structural change of the tail tube induced by its interaction with the S. aureus cell is required for the genome’s release.

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“…Representatives of the two genera share the following features: they (i) have large genomes (127 to 140 kb), (ii) are strictly virulent, (iii) infect Gram-positive, low-GC-content bacteria, (iv) have a wide host range among strains of the susceptible bacterial genus, and (v) share considerable similarities at the protein sequence level (7). Thanks to their wide host range and highly lytic capabilities, phages in these genera, including ⌽SA012, are considered to be promising candidates for therapeutic use and as detection agents (8,9).The infection process of phages can be divided into the following steps: phage adsorption to the host, DNA injection into the host cell, DNA replication, assembly of phage particles, and lysis of the host cell. Because adsorption of a phage to the host, caused by the interaction between a phage receptor on the bacterial surface and receptor-binding proteins (RBPs) in the tips of the tail fibers or tail spikes, is extremely specific, RBPs determine the target bacteria for phage infection (10).…”

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confidence: 99%

mentioning

confidence: 99%

The Presence of Two Receptor-Binding Proteins Contributes to the Wide Host Range of Staphylococcal Twort-Like Phages

Takeuchi

Osada

Azam

et al. 2016

Appl Environ Microbiol

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Thanks to their wide host range and virulence, staphylococcal bacteriophages (phages) belonging to the genus Twortlikevirus (staphylococcal Twort-like phages) are regarded as ideal candidates for clinical application for Staphylococcus aureus infections due to the emergence of antibiotic-resistant bacteria of this species. To increase the usability of these phages, it is necessary to understand the mechanism underlying host recognition, especially the receptor-binding proteins (RBPs) that determine host range. In this study, we found that the staphylococcal Twort-like phage ⌽SA012 possesses at least two RBPs. Genomic analysis of five mutant phages of ⌽SA012 revealed point mutations in orf103, in a region unique to staphylococcal Twort-like phages. Phages harboring mutated ORF103 could not infect S. aureus strains in which wall teichoic acids (WTAs) are glycosylated with ␣-N-acetylglucosamine (␣-GlcNAc). A polyclonal antibody against ORF103 also inhibited infection by ⌽SA012 in the presence of ␣-GlcNAc, suggesting that ORF103 binds to ␣-GlcNAc. In contrast, a polyclonal antibody against ORF105, a short tail fiber component previously shown to be an RBP, inhibited phage infection irrespective of the presence of ␣-GlcNAc. Immunoelectron microscopy indicated that ORF103 is a tail fiber component localized at the bottom of the baseplate. From these results, we conclude that ORF103 binds ␣-GlcNAc in WTAs, whereas ORF105, the primary RBP, is likely to bind the WTA backbone. These findings provide insight into the infection mechanism of staphylococcal Twort-like phages. IMPORTANCE Staphylococcus phages belonging to the genus Staphylococcus aureus, a Gram-positive coccus, is a commensal and pathogenic bacterium that causes opportunistic infections in humans and animals. Currently, antibiotic resistance in this species poses a threat to public health. Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired infections around the world (1). The emergence of such antibiotic-resistant bacteria requires development of alternatives to antibiotic-based therapies. One promising alternative is phage therapy, in which bacteriophages (phages) are used to treat bacterial infections (2, 3). In preclinical trials performed in mice, S. aureus infections (including MRSA infections) were successfully treated by use of phages (4). Therefore, phage therapy has attracted great interest as an alternative to antibiotics.Previously, we isolated the virulent staphylococcal phage ⌽SA012, which exerts lytic effects on a wide range of S. aureus isolates from bovine mastitis cases (5). Genomic analysis of ⌽SA012 revealed that it belongs to the genus Twortlikevirus, which contains the Staphylococcus phages Twort, K, and G, whereas the genus SPO1likevirus contains the Bacillus phage SPO1 as well as Listeria phages P100 and A511. Lactobacillus phage LP65 and Enterococcus phage ⌽EF24C were classified as orphans within the subfamily (6). Representatives of the two genera share the following features: they (i) hav...

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Combined Use of Bacteriophage K and a Novel Bacteriophage To Reduce Staphylococcus aureus Biofilm Formation

Cited by 155 publications

References 64 publications

Low-level predation by lytic phage phiIPLA-RODI promotes biofilm formation and triggers the stringent response in Staphylococcus aureus

Low-level predation by lytic phage phiIPLA-RODI promotes biofilm formation and triggers the stringent response in Staphylococcus aureus

Structure and genome release of Twort-like Myoviridae phage with a double-layered baseplate

The Presence of Two Receptor-Binding Proteins Contributes to the Wide Host Range of Staphylococcal Twort-Like Phages

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