Pharmacokinetics of the phage endolysin‐based candidate drug <scp>SAL</scp>200 in monkeys and its appropriate intravenous dosing period

Jun, Soo Youn; Jung, Gi Mo; Yoon, Seong Jun; Youm, So Young; Han, Hyoung-Yun; Lee, Jong-Hwa; Kang, Sang Hoon

doi:10.1111/1440-1681.12613

Cited by 32 publications

(26 citation statements)

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“…Nonetheless, after the injection of SAL200, the symptoms were observed only transiently and were considered mild (146). In a further safety and pharmacokinetic study conducted in monkeys, SAL200 was well tolerated and did not cause any adverse effects when injected as a single dose (up to 80 mg/kg body weight) or as multiple doses, up to 40 mg/kg per day (138). Most recently, SAL200 became the first endolysin-based drug applied to humans by intravenous infusion as part of a phase 1 clinical trial (140).…”

Section: In Vivo Studies With Lysk and Its Derivatives And Homologuesmentioning

confidence: 95%

“…Mutation of the respective residues abolished the binding of the CBD to S. aureus peptidoglycan (91). Besides LysGH15, another LysK homologue, named SAL-1, was recently described and extensively characterized (137)(138)(139). This endolysin differs from LysK in only 3 amino acids; however, it was claimed by those authors to exhibit higher activity against multiple S. aureus strains than LysK (139).…”

Section: Lysk and Its Homologues Structure Function And Physicochemmentioning

confidence: 99%

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Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies

et al. 2018

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is one of the most common pathogens of humans and animals, where it frequently colonizes skin and mucosal membranes. It is of major clinical importance as a nosocomial pathogen and causative agent of a wide array of diseases. Multidrug-resistant strains have become increasingly prevalent and represent a leading cause of morbidity and mortality. For this reason, novel strategies to combat multidrug-resistant pathogens are urgently needed. Bacteriophage-derived enzymes, so-called endolysins, and other peptidoglycan hydrolases with the ability to disrupt cell walls represent possible alternatives to conventional antibiotics. These lytic enzymes confer a high degree of host specificity and could potentially replace or be utilized in combination with antibiotics, with the aim to specifically treat infections caused by Gram-positive drug-resistant bacterial pathogens such as methicillin-resistant . LysK is one of the best-characterized endolysins with activity against multiple staphylococcal species. Various approaches to further enhance the antibacterial efficacy and applicability of endolysins have been demonstrated. These approaches include the construction of recombinant endolysin derivatives and the development of novel delivery strategies for various applications, such as the production of endolysins in lactic acid bacteria and their conjugation to nanoparticles. These novel strategies are a major focus of this review.

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Section: In Vivo Studies With Lysk and Its Derivatives And Homologuesmentioning

confidence: 95%

Section: Lysk and Its Homologues Structure Function And Physicochemmentioning

confidence: 99%

Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies

et al. 2018

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“…This study also assessed the safety and tolerability of SAL200 endolysin after intravenous administration of a single dose of 1 to 80 mg/kg/day for 6 days or multiple doses of 40 mg/kg/day for 5 days. The protein was well tolerated, and no adverse effects were detected ( 59 ).…”

Section: Therapeutic Efficacy Of Phage Lytic Proteinsmentioning

confidence: 99%

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

Gutiérrez

Fernández

Rodrı́guez

et al. 2018

mBio

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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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“…The rapid and effective bactericidal activity of SAL200 suggests that a brief SAL200 dosing period is sufficient to treat staphylococcal infections. In addition, favorable safety evaluation results were obtained in good laboratory practice (GLP)-compliant studies that evaluated the safety of intravenously administered SAL200 in rats (26), dogs (26), and monkeys (27). …”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers

Jun

Jang

Yoon

et al. 2017

Antimicrob Agents Chemother

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125

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This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.).

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Pharmacokinetics of the phage endolysin‐based candidate drug SAL200 in monkeys and its appropriate intravenous dosing period

Cited by 32 publications

References 5 publications

Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies

Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies

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

Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers

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