Bacteriophage-host arm race: an update on the mechanism of phage resistance in bacteria and revenge of the phage with the perspective for phage therapy

Azam, Aa Haeruman; Tanji, Yasunori

doi:10.1007/s00253-019-09629-x

Cited by 170 publications

(144 citation statements)

References 89 publications

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“…In addition to specialized phage defense mechanisms, bacteria also use physical shields. Commonly produced by Gram-negative bacteria OMVs (outer-membrane vesicles) mislead attacking viruses that inject their genetic material into an empty vesicle [2]. The bacterial biofilm, which mechanically limits the access to the receptors recognized by phages, also plays a very important protective role.…”

Section: Introductionmentioning

confidence: 99%

Pseudomonas aeruginosa PA5oct Jumbo Phage Impacts Planktonic and Biofilm Population and Reduces Its Host Virulence

Olszak

Danis-Wlodarczyk

Arabski

et al. 2019

Viruses

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The emergence of phage-resistant mutants is a key aspect of lytic phages-bacteria interaction and the main driver for the co-evolution between both organisms. Here, we analyze the impact of PA5oct jumbo phage treatment on planktonic/cell line associated and sessile P. aeruginosa population. Besides its broad-spectrum activity and efficient bacteria reduction in both airway surface liquid (ASL) model, and biofilm matrix degradation, PA5oct appears to persist in most of phage-resistant clones. Indeed, a high percentage of resistance (20/30 clones) to PA5oct is accompanied by the presence of phage DNA within bacterial culture. Moreover, the maintenance of this phage in the bacterial population correlates with reduced P. aeruginosa virulence, coupled with a sensitization to innate immune mechanisms, and a significantly reduced growth rate. We observed rather unusual consequences of PA5oct infection causing an increased inflammatory response of monocytes to P. aeruginosa. This phenomenon, combined with the loss or modification of the phage receptor, makes most of the phage-resistant clones significantly less pathogenic in in vivo model. These findings provide new insights into the general knowledge of giant phages biology and the impact of their application in phage therapy.

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Section: Introductionmentioning

confidence: 99%

Pseudomonas aeruginosa PA5oct Jumbo Phage Impacts Planktonic and Biofilm Population and Reduces Its Host Virulence

Olszak

Danis-Wlodarczyk

Arabski

et al. 2019

Viruses

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“…Bacteria can resist phage infection through different mechanisms, including (i) spontaneous mutations to prevent phage adsorption or phage DNA entry, (ii) restriction modification systems to cut phage nucleic acids, and (iii) CRISPR-Cas system mediated adaptive immunity (49)(50)(51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of inhaled antipseudomonal bacteriophage therapy in mice

Chow

Chang

et al. 2020

Preprint

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Inhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR) Pseudomonas aeruginosa infections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different to antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study was to investigate the in vivo PK and PD profiles of antipseudomonal phage PEV31 delivered by pulmonary route in mice. BALB/c mice were administered phage PEV31 at doses of 107 and 109 PFU by the intratracheal route. Mice (n = 4) were sacrificed at 0, 1, 2, 4, 8 and 24 h post-treatment and various tissues (lungs, kidney, spleen and liver), bronchoalveolar lavage and blood were collected for phage quantification. In a separate study, mice (n = 4) were treated with PEV31 (109 PFU) or PBS at 2 h post-inoculation with MDR P. aeruginosa. Infective PEV31 and bacteria were enumerated from the lungs. In the phage only study, PEV31 titer gradually decreased in the lungs over 24 hours with a half-life of approximately 8 h for both doses. In the presence of bacteria, PEV31 titer increased by almost 2-log10 in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Some phage-resistant colonies were observed from the lung homogenates sampled at 24 h post-phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.

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“…Although ɸSA039 requires the β-GlcNAc moiety in WTA of S. aureus , it can switch its receptor by acquiring spontaneous mutation in its RBP. Alteration of phage receptors is a bacterial strategy used to prevent the initial step of phage infection (Capparelli et al 2010; Hyman and Abedon 2010; Azam and Tanji 2019a). A previous study showed that spontaneous mutant S. aureus lacking the β-GlcNAc moiety in WTA can be easily obtained by co-culturing the bacteria with phage (Azam et al 2018), suggesting that the emergence of phage-resistant S. aureus lacking β-GlcNAc moiety in WTA is possible in a real-world setting.…”

Section: Discussionmentioning

confidence: 99%

“…Infection by S. aureus and S. pseudintermedius is becoming problematic due to the emergence of antibiotic-resistant strains, including methicillin-resistant (MRSA and MRSP) and vancomycin-resistant strains (VRSA) (Enright et al 2002; Sakoulas et al 2005). Virulent bacteriophages that can kill a wide range of S. aureus hosts represent promising alternatives to conventional antibiotic treatment (Alves et al 2014; Iwano et al 2018; Azam and Tanji 2019a). The success of phage infection depends on its host specificity, which is often determined by the interaction between a phage receptor-binding protein (RBP) and its cognate receptor on the surface of the host cell (Hyman and Abedon 2010).…”

Section: Introductionmentioning

confidence: 99%

Analysis host-recognition mechanism of staphylococcal kayvirus ɸSA039 reveals a novel strategy that protects Staphylococcus aureus against infection by Staphylococcus pseudintermedius Siphoviridae phages

Azam

Kadoi

Miyanaga

et al. 2019

Preprint

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1 reveals a novel strategy that protects Staphylococcus aureus against infection 2 by Staphylococcus pseudintermedius Siphoviridae phages 3 4 5 6 Abstract 21Following the emergence of antibiotic resistant bacteria such as methicillin-resistant 22 Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus pseudintermedius 23 (MRSP), phage therapy has attracted significant attention as an alternative to antibiotic 24 treatment. Bacteriophages belonging to kayvirus (previously known as Twort-like phages) have 25 broad host range and are strictly lytic in Staphylococcus spp. Previous work revealed that 26 kayvirus ɸSA039 has a host-recognition mechanism distinct from those of other known 27 kayviruses: most of kayviruses use the backbone of wall teichoic acid (WTA) as their receptor; 28 by contrast, ɸSA039 uses the β-N-acetylglucosamine (β-GlcNAc) residue in WTA. In this study, 29 we found that ɸSA039 could switch its receptor to be able to infect S. aureus lacking the β- 30 GlcNAc residue by acquiring a spontaneous mutation in open reading frame (ORF) 100 and 31 ORF102. Moreover, ɸSA039 could infect S. pseudintermedius, which has a different WTA 32 structure than S. aureus. By comparison with newly isolated S. pseudintermedius-specific phage 33 (SP phages), we determined that glycosylation in WTA of S. pseudintermedius is essential for 34 adsorption of SP phages, but not ɸSA039. Finally, we describe a novel strategy of S. aureus 35 which protects the bacteria from infection of SP phages. Notably, glycosylation of ribitol 36 phosphate (RboP) WTA by TarM or/and TarS prevents infection of S. aureus by SP phages. 37 These findings could help to establish a new strategy for treatment of S. aureus and S. 38 pseudintermedius infection, as well as provide valuable insights into the biology of phage-host 39 interactions. 40 Keyword: Kayvirus, phage therapy, host-recognition mechanism, Staphylococcus 41 pseudintermedius, Staphylococcus aureus 42 43Staphylococcus is a Gram-positive bacterium that causes many kinds of infections. Two 45 representative species, S. aureus and S. pseudintermedius, are coagulase-positive bacteria that 46 are notoriously pathogenic in humans and animals (Kloos and Bannerman 1994; Pompilio et al. 47 2015). S. aureus is a commensal found on the skin and mucosae of humans, whereas S. 48 pseudintermedius commonly inhabits dog skin. Both are common bacterial pathogens associated 49 with chronic and recurrent skin infections that require long-term systemic antimicrobial therapy. 50Infection by S. aureus and S. pseudintermedius is becoming problematic due to the emergence of 51 antibiotic-resistant strains, including methicillin-resistant (MRSA and MRSP) and vancomycin-52 resistant strains (VRSA) (Enright et al. 2002; Sakoulas et al. 2005). Virulent bacteriophages that 53 can kill a wide range of S. aureus hosts represent promising alternatives to conventional 54 antibiotic treatment (Alves et al. 2014; Iwano et al. 2018; Azam and Tanji 2019a). The success 55 of p...

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Bacteriophage-host arm race: an update on the mechanism of phage resistance in bacteria and revenge of the phage with the perspective for phage therapy

Cited by 170 publications

References 89 publications

Pseudomonas aeruginosa PA5oct Jumbo Phage Impacts Planktonic and Biofilm Population and Reduces Its Host Virulence

Pseudomonas aeruginosa PA5oct Jumbo Phage Impacts Planktonic and Biofilm Population and Reduces Its Host Virulence

Pharmacokinetics and pharmacodynamics of inhaled antipseudomonal bacteriophage therapy in mice

Analysis host-recognition mechanism of staphylococcal kayvirus ɸSA039 reveals a novel strategy that protects Staphylococcus aureus against infection by Staphylococcus pseudintermedius Siphoviridae phages

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