Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii

Defraine, Valerie; Schuermans, J; Grymonprez, Barbara; Govers, Sander K.; Aertsen, Abram; Fauvart, Maarten; Michiels, Jan; Lavigne, Rob; Briers, Yves

doi:10.1128/aac.00285-16

Cited by 112 publications

(100 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They kill bacteria faster than antibiotics, and resistance to lysins is a rare event due to the conserved nature of their peptidoglycan target. Resistance has not been observed for lysins targeting Gram-positive bacteria (15,17) or for the Gram-negative bacterial Artilysin Art-175 when tested against P. aeruginosa and A. baumannii (38,39). Because of their broad activity against Klebsiella and Enterobacter strains, in addition to P. aeruginosa, the enzymes described in this study hold promise as new agents to control a range of topical and mucosal MDR Gram-negative bacterial infections.…”

Section: Discussionmentioning

confidence: 91%

Isolation of Phage Lysins That Effectively Kill Pseudomonas aeruginosa in Mouse Models of Lung and Skin Infection

Raz

Serrano

Hernandez

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Multidrug resistance (MDR) is rapidly increasing in prevalence among isolates of the opportunistic pathogen Pseudomonas aeruginosa, leaving few treatment options. Phage lysins are cell wall hydrolases that have a demonstrated therapeutic potential against Gram-positive pathogens; however, the outer membrane of Gram-negative bacteria prevents most lysins from reaching the peptidoglycan, making them less effective as therapeutics. Nevertheless, a few lysins from Gram-negative bacterial phage can penetrate the bacterial outer membrane with the aid of an amphipathic tail found in the molecule’s termini. In this work, we took a phylogenetic approach to systematically identify those lysins from P. aeruginosa phage that would be most effective therapeutically. We isolated and performed preliminary characterization of 16 lysins and chose 2 lysins, PlyPa03 and PlyPa91, which exhibited >5-log killing activity against P. aeruginosa and other Gram-negative pathogens (particularly Klebsiella and Enterobacter). These lysins showed rapid killing kinetics and were active in the presence of high concentrations of salt and urea and under pH conditions ranging from 5.0 to 10.0. Activity was not inhibited in the presence of the pulmonary surfactant beractant (Survanta). While neither enzyme was active in 100% human serum, PlyPa91 retained activity in low serum concentrations. The lysins were effective in the treatment of a P. aeruginosa skin infection in a mouse model, and PlyPa91 protected mice in a lung infection model, making these lysins potential drug candidates for Gram-negative bacterial infections of the skin or respiratory mucosa.

show abstract

Section: Discussionmentioning

confidence: 91%

Isolation of Phage Lysins That Effectively Kill Pseudomonas aeruginosa in Mouse Models of Lung and Skin Infection

Raz

Serrano

Hernandez

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…A more rational approach was used in the development of the artilysin Art-175, consisting of a bacteriophage genome-encoded endolysin coupled to a peptide for guidance through the bacterial outer membrane. Art-175 is capable of puncturing the peptidoglycan, resulting in cell lysis, and was shown to be active against persister cells of both P. aeruginosa (24) and Acinetobacter baumannii (35). Another target-based approach led to the identification of a group of quorum-sensing (QS) inhibitors that specifically target the P. aeruginosa MvfR system.…”

Section: Discussionmentioning

confidence: 99%

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Liebens

Defraine

Knapen

et al. 2017

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen to be a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current study focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and, due to increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of P. aeruginosa infections is the presence of persister cells, and elimination of these cells would therefore significantly improve patient outcomes. In this study, a smallmolecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of P. aeruginosa persisters compared to the number achieved with treatment with the antibiotic alone. Based on the early structure-activity relationship, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 10 6 -fold in both lab strains and clinical isolates of P. aeruginosa. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. In conclusion, we identified a novel antipersister compound active against P. aeruginosa with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections.

show abstract

“…Artilysins are engineered fusions of bacteriophage-encoded endolysins, which degrade peptidoglycans of the bacterial cells wall, with specific AMPs, which facilitate the transduction of the endolysin through the protective outer membrane of Gram-negative pathogens to reach its substrate (Briers et al, 2014a,b; Briers and Lavigne, 2015; Defraine et al, 2016). …”

Section: Mechanism Of Action Of Ampsmentioning

confidence: 99%

Antimicrobial Peptides: An Emerging Category of Therapeutic Agents

Mahlapuu

Håkansson

Ringstad

et al. 2016

Front. Cell. Infect. Microbiol.

1,406

1,316

View full text Add to dashboard Cite

Antimicrobial peptides (AMPs), also known as host defense peptides, are short and generally positively charged peptides found in a wide variety of life forms from microorganisms to humans. Most AMPs have the ability to kill microbial pathogens directly, whereas others act indirectly by modulating the host defense systems. Against a background of rapidly increasing resistance development to conventional antibiotics all over the world, efforts to bring AMPs into clinical use are accelerating. Several AMPs are currently being evaluated in clinical trials as novel anti-infectives, but also as new pharmacological agents to modulate the immune response, promote wound healing, and prevent post-surgical adhesions. In this review, we provide an overview of the biological role, classification, and mode of action of AMPs, discuss the opportunities and challenges to develop these peptides for clinical applications, and review the innovative formulation strategies for application of AMPs.

show abstract

Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii

Cited by 112 publications

References 49 publications

Isolation of Phage Lysins That Effectively Kill Pseudomonas aeruginosa in Mouse Models of Lung and Skin Infection

Isolation of Phage Lysins That Effectively Kill Pseudomonas aeruginosa in Mouse Models of Lung and Skin Infection

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Antimicrobial Peptides: An Emerging Category of Therapeutic Agents

Contact Info

Product

Resources

About