A novel chimeric lysin with robust antibacterial activity against planktonic and biofilm methicillin-resistant Staphylococcus aureus

Yang, Hang; Zhang, Huaidong; Wang, Jing; Yu, Junping; Wei, Hongping

doi:10.1038/srep40182

Cited by 68 publications

(59 citation statements)

References 62 publications

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“…The inhibitory effect of P128 on CoNS biofilms was maintained for 24 h. The percent reduction in OD 540 values (Table S6) shows that P128 consistently caused a reduction in OD at 24 h, ranging from 70 to 93%, in all three CoNS strains. A recently reported chimeric lysin, ClyF, at high concentration (100 g/ml) was shown to remove biofilm biomass of S. aureus and CoNS species in a similar assay (33). In our study, linezolid did not reduce the biomass even after 24 h, as there was no significant reduction in OD 540 values in any of the strains (Fig.…”

supporting

confidence: 78%

Efficient Killing of Planktonic and Biofilm-Embedded Coagulase-Negative Staphylococci by Bactericidal Protein P128

Poonacha¹,

Nair²,

Desai³

et al. 2017

Antimicrob Agents Chemother

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Coagulase-negative staphylococci (CoNS) are the major causative agents of foreign-body-related infections, including catheter-related bloodstream infections. Because of the involvement of biofilms, foreign-body-related infections are difficult to treat. P128, a chimeric recombinant phage-derived ectolysin, has been shown to possess bactericidal activity on strains of Staphylococcus aureus, including methicillinresistant S. aureus (MRSA). We tested the killing potential of P128 on three clinically significant species of CoNS, S. epidermidis, S. haemolyticus, and S. lugdunensis, under a variety of physiological conditions representing growing and nongrowing states. The MIC 90 and minimum bactericidal concentration at which 90% of strains tested are killed (MBC 90 ) of P128 on 62 clinical strains of CoNS were found to be 16 and 32 g/ml (0.58 and 1.16 M), respectively, demonstrating the bactericidal nature of P128 on CoNS strains. Serum showed a potentiating effect on P128 inhibition, as indicated by 4-to 32-fold lower MIC values observed in serum. P128 caused a rapid loss of viability in all CoNS strains tested. Persisters of CoNS that were enriched in the presence of vancomycin or daptomycin were killed by P128 at 1ϫ the MIC in a rapid manner. Low concentrations of P128 caused a 2-to 5-log reduction in CFU in stationary-phase or poorly metabolizing CoNS cultures. P128 at low concentrations eliminated CoNS biofilms in microtiter plates and on the surface of catheters. Combinations of P128 and standard-of-care (SoC) antibiotics were highly synergistic in inhibiting growth in preformed biofilms. Potent activity on planktonic cells, persisters, and biofilms of CoNS suggests that P128 is a promising candidate for the clinical development of treatments for foreign-body-related and other CoNS infections.

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supporting

confidence: 78%

Efficient Killing of Planktonic and Biofilm-Embedded Coagulase-Negative Staphylococci by Bactericidal Protein P128

Poonacha¹,

Nair²,

Desai³

et al. 2017

Antimicrob Agents Chemother

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“…Many reports noted that both S. aureus and S. epidermidis could be killed by lysins of S. aureus phages, which included LysH5 (22), LysKΔamidase (23), P128 (10), PlyGRCS (35), SAL-2 (36), and ClyF (25), as well as the lysins of phages 80␣, ⌽11, K, P68, Twort, PhiSH2, and WMY (37). Additionally, S. epidermidis phage-derived lysins, such as Andhra_gp14 and Andhra_gp10 (38), also showed bactericidal activity against S. aureus and S. epidermidis.…”

Section: Discussionmentioning

confidence: 99%

“…The results obtained by SEM, CLSM, and OD 590 detection indicated the continued presence of biofilms, which could be attributed to LysGH15 insufficiency because the remaining cells and biofilms were also sensitive to LysGH15 (data not shown). Thus far, several lysins, including LysKΔamidase (23), LysH5 (22), LysSA97 (40), and ClyF (25), have been reported to be able to remove biofilms formed by S. aureus and/or S. epidermidis. LysGH15 showed biofilm elimination ability similar to or better than those of these lysins.…”

Section: Discussionmentioning

confidence: 99%

“…Due to their high efficiency, lack of resistance, lack of neutralizing antibodies, and specificity, lysins hold great therapeutic potential for bacterial infections caused by antibiotic-resistant strains. Additionally, it has been reported that several staphylococcal phage-derived lysins, such as LysH5 (22), LysKΔamidase (23), P128 (10), PlySs2 (24), and ClyF (25), possess the ability to clear biofilms.…”

mentioning

confidence: 99%

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Antibacterial Effects of Phage Lysin LysGH15 on Planktonic Cells and Biofilms of Diverse Staphylococci

Zhang

Cheng

Zhang

et al. 2018

Appl Environ Microbiol

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Treatment of infections caused by staphylococci has become more difficult because of the emergence of multidrug-resistant strains as well as biofilm formation. In this study, we observed the ability of the phage lysin LysGH15 to eliminate staphylococcal planktonic cells and biofilms formed by ,, , and All these strains were sensitive to LysGH15, showing reductions in bacterial counts of approximately 4 log units within 30 min after treatment with 20 μg/ml of LysGH15, and the MICs ranged from 8 μg/ml to 32 μg/ml. LysGH15 efficiently prevented biofilm formation by the four staphylococcal species at a dose of 50 μg/ml. At a higher dose (100 μg/ml), LysGH15 also showed notable disrupting activity against 24-h and 72-h biofilms formed by and coagulase-negative species. In the experiments, a single intraperitoneal injection of LysGH15 (20 μg/mouse) administered 1 h after the injection of at double the minimum lethal dose was sufficient to protect the mice. The cell counts were 4 log units lower in the blood and 3 log units lower in the organs of mice 24 h after treatment with LysGH15 than in the untreated control mice. LysGH15 reduced cytokine levels in the blood and improved pathological changes in the organs. The broad antistaphylococcal activity exerted by LysGH15 on planktonic cells and biofilms makes LysGH15 a valuable treatment option for biofilm-related or non-biofilm-related staphylococcal infections. Most staphylococcal species are major causes of health care- and community-associated infections. In particular, is a common and dangerous pathogen, and is a ubiquitous skin commensal and opportunistic pathogen. Treatment of infections caused by staphylococci has become more difficult because of the emergence of multidrug-resistant strains as well as biofilm formation. In this study, we found that all tested ,, , and strains were sensitive to the phage lysin LysGH15 (MICs ranging from 8 to 32 μg/ml). More importantly, LysGH15 not only prevented biofilm formation by these staphylococci but also disrupted 24-h and 72-h biofilms. Furthermore, the efficacy of LysGH15 was demonstrated in a mouse model of bacteremia. Thus, LysGH15 exhibits therapeutic potential for treating biofilm-related or non-biofilm-related infections caused by diverse staphylococci.

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“…In this context, there is considerable evidence with regard to the efficacy of phage lytic proteins against preformed S. aureus biofilms. Some of the proteins with proven antibiofilm properties are endolysins SAL-2, phi11, PlyGRCS, and SAL200, as well as the chimeric proteins Chapter K (derived from LysK), ClyH (derived from the Ply187 and phiNM3 endolysins), and ClyF (derived from the Ply187 and PlySs2 endolysins) ( 29 – 35 ). In the case of the chimeric protein ClyH, the susceptibilities of biofilms turned out to be dependent on the strain and the biofilm maturation stage.…”

Section: Main Characteristics and Properties Of S Aureusmentioning

confidence: 99%

Are Phage Lytic Proteins the Secret Weapon To Kill Staphylococcus aureus ?

Gutiérrez

Fernández

Rodrı́guez

et al. 2018

mBio

117

107

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Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most threatening microorganisms for global human health. The current strategies to reduce the impact of S. aureus include a restrictive control of worldwide antibiotic use, prophylactic measures to hinder contamination, and the search for novel antimicrobials to treat human and animal infections caused by this bacterium. The last strategy is currently the focus of considerable research. In this regard, phage lytic proteins (endolysins and virion-associated peptidoglycan hydrolases [VAPGHs]) have been proposed as suitable candidates. Indeed, these proteins display narrow-spectrum antimicrobial activity and a virtual lack of bacterial-resistance development. Additionally, the therapeutic use of phage lytic proteins in S. aureus animal infection models is yielding promising results, showing good efficacy without apparent side effects. Nonetheless, human clinical trials are still in progress, and data are not available yet. This minireview also analyzes the main obstacles for introducing phage lytic proteins as human therapeutics against S. aureus infections. Besides the common technological problems derived from large-scale production of therapeutic proteins, a major setback is the lack of a proper legal framework regulating their use. In that sense, the relevant health authorities should urgently have a timely discussion about these new antimicrobials. On the other hand, the research community should provide data to dispel any doubts regarding their efficacy and safety. Overall, the appropriate scientific data and regulatory framework will encourage pharmaceutical companies to invest in these promising antimicrobials.

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A novel chimeric lysin with robust antibacterial activity against planktonic and biofilm methicillin-resistant Staphylococcus aureus

Cited by 68 publications

References 62 publications

Efficient Killing of Planktonic and Biofilm-Embedded Coagulase-Negative Staphylococci by Bactericidal Protein P128

Efficient Killing of Planktonic and Biofilm-Embedded Coagulase-Negative Staphylococci by Bactericidal Protein P128

Antibacterial Effects of Phage Lysin LysGH15 on Planktonic Cells and Biofilms of Diverse Staphylococci

Are Phage Lytic Proteins the Secret Weapon To Kill Staphylococcus aureus ?

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