The N-terminal and central domain of colicin A enables phage lysin to lyse Escherichia coli extracellularly

Yan, Guangmou; Liu, Jianfang; Ma, Qiang; Zhu, Rining; Guo, Zhimin; Gao, Chencheng; Wang, Shuang; Yu, Ling; Gu, Jingmin; Hu, Dong‐Liang; Wang, Han; Du, Rui; Yang, Junling; Lei, Liancheng

doi:10.1007/s10482-017-0912-9

Cited by 37 publications

(38 citation statements)

References 35 publications

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“…Unfortunately, like most Gram-negative lysins, Artilysins appear to be inactive in human serum (HuS), limiting their therapeutic applicability to superficial, nonsystemic bacterial infections (8)(9)(10). An alternative engineering strategy has been described using bacteriocin-lysin hybrid molecules to actively transport lysins across protein channels embedded in the OM of Gram-negative bacteria (11,12). For instance, the construction of a lysin-colicin A chimeric molecule yielded a construct (Colicin-Lysep3) capable of traversing the OM of Escherichia coli.…”

mentioning

confidence: 99%

Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria

Heselpoth

Euler

Schuch

et al. 2019

Antimicrob Agents Chemother

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The prevalence of multidrug-resistant Pseudomonas aeruginosa has stimulated development of alternative therapeutics. Bacteriophage peptidoglycan hydrolases, termed lysins, represent an emerging antimicrobial option for targeting Gram-positive bacteria. However, lysins against Gram-negatives are generally deterred by the outer membrane and their inability to work in serum. One solution involves exploiting evolved delivery systems used by colicin-like bacteriocins (e.g., S-type pyocins of P. aeruginosa) to translocate through the outer membrane. Following surface receptor binding, colicin-like bacteriocins form Tol-or TonB-dependent translocons to actively import bactericidal domains through outer membrane protein channels. With this understanding, we developed lysocins, which are bioengineered lysin-bacteriocin fusion molecules capable of periplasmic import. In our proof-ofconcept studies, components from the P. aeruginosa bacteriocin pyocin S2 (PyS2) responsible for surface receptor binding and outer membrane translocation were fused to the GN4 lysin to generate the PyS2-GN4 lysocin. PyS2-GN4 delivered the GN4 lysin to the periplasm to induce peptidoglycan cleavage and log-fold killing of P. aeruginosa with minimal endotoxin release. While displaying narrow-spectrum antipseudomonal activity in human serum, PyS2-GN4 also efficiently disrupted biofilms, outperformed standard-of-care antibiotics, exhibited no cytotoxicity toward eukaryotic cells, and protected mice from P. aeruginosa challenge in a bacteremia model. In addition to targeting P. aeruginosa, lysocins can be constructed to target other prominent Gram-negative bacterial pathogens.A ntimicrobial resistance is a threat to global public health. One of the predominant antibiotic-resistant microorganisms responsible for high mortality rates is Pseudomonas aeruginosa. This Gram-negative pathogen is (i) the leading cause of mortality in cystic fibrosis patients, (ii) the main causative agent of burn wound infections, (iii) the most frequent Gram-negative bacterium associated with nosocomial and ventilatoracquired pneumonia, and (iv) the second most common cause of catheter-associated urinary tract infections (1). Additionally, P. aeruginosa is responsible for 3 to 7% of all bloodstream infections (BSIs) and 23 to 26% of Gram-negative bacteremias, translating to mortality rates ranging from 27 to 48% (2). With the antipseudomonal efficacy of standard-of-care (SOC) antibiotics progressively diminishing due to a combination of intrinsic, acquired, and adaptive resistance mechanisms utilized by the bacteria, the lack of therapeutic options has stimulated the World Health Organization to label P. aeruginosa as a critical priority for the research, discovery, and development of new antibiotics (3, 4).

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confidence: 99%

Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria

Heselpoth

Euler

Schuch

et al. 2019

Antimicrob Agents Chemother

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“…Lysins may be engineered to penetrate and kill Gram-negative bacteria by exploiting colicin-like bacteriocins, which actively transverse the bacterial OM to deliver lysins to the peptidoglycan in the periplasmic space [34,65,66]. The first successful example of this type of hybrid lysin was the fusion of a binding domain from pesticin, a FyuA outer membrane transporter binding protein from Yersinia pestis, to the N-terminus of T4 bacteriophage lysozyme.…”

Section: Lysocinsmentioning

confidence: 99%

“…This Pesticin-T4 lysozyme toxin was able to be transported across the outer membrane and kill Y. pestis in vitro, as well as other Yersiniae and E. coli isolates expressing the FyuA receptor [65]. Similarly, the Lysep3 coliphage lysin described above was also further modified to include the receptor binding and translocation domains of Colicin A, allowing it to translocate into the periplasmim and kill E. coli isolates from farms in in vitro assays [66] Furthermore, this hybrid lysin also reduced the amount of fluorescent E. coli in a mouse intestinal infection model. Recently, to address the concerns of MDR P. aeruginosa, another proof of concept study was initiated to fuse the P. aeruginosa phage PAJU2 muramidase GN4 to the P. aeruginosa bacteriocin pyocin S2 (PyS2) [34].…”

Section: Lysocinsmentioning

confidence: 99%

Gram-Negative Bacterial Lysins

Ghose¹,

Euler

2020

Antibiotics

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Antibiotics have had a profound impact on human society by enabling the eradication of otherwise deadly infections. Unfortunately, antibiotic use and overuse has led to the rapid spread of acquired antibiotic resistance, creating a major threat to public health. Novel therapeutic agents called bacteriophage endolysins (lysins) provide a solution to the worldwide epidemic of antibiotic resistance. Lysins are a class of enzymes produced by bacteriophages during the lytic cycle, which are capable of cleaving bonds in the bacterial cell wall, resulting in the death of the bacteria within seconds after contact. Through evolutionary selection of the phage progeny to be released and spread, these lysins target different critical components in the cell wall, making resistance to these molecules orders of magnitude less likely than conventional antibiotics. Such properties make lysins uniquely suitable for the treatment of multidrug resistant bacterial pathogens. Lysins, either naturally occurring or engineered, have the potential of being developed into fast-acting, narrow-spectrum, biofilm-disrupting antimicrobials that act synergistically with standard of care antibiotics. This review focuses on newly discovered classes of Gram-negative lysins with emphasis on prototypical enzymes that have been evaluated for efficacy against the major antibiotic resistant organisms causing nosocomial infections.

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“…Depolymerase producing K. pneumoniae phage, in combination with iron antagonizing agents, showed ability to eradicate early biofilms of K. pneumoniae : a promising preventative strategy (Chhibber et al, 2013 ). Progress has also been made in lysin research: Yan et al described a novel fusion protein that combines the receptor binding domains of colicin A with an E. coli phage lysin to overcome the blocking effect of the Gram-negative outer membrane, with successful control of E. coli both in vitro and in a mouse model (Yan et al, 2017 ).…”

Section: The Challenge Of Multi-drug Resistant Bacteriamentioning

confidence: 99%

Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles

Furfaro

Payne

Chang

2018

Front. Cell. Infect. Microbiol.

249

179

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Increasing reports of antimicrobial resistance and limited new antibiotic discoveries and development have fuelled innovation in other research fields and led to a revitalization of bacteriophage (phage) studies in the Western world. Phage therapy mainly utilizes obligately lytic phages to kill their respective bacterial hosts, while leaving human cells intact and reducing the broader impact on commensal bacteria that often results from antibiotic use. Phage therapy is rapidly evolving and has resulted in cases of life-saving therapeutic use and multiple clinical trials. However, one of the biggest challenges this antibiotic alternative faces relates to regulations and policy surrounding clinical use and implementation beyond compassionate cases. This review discusses the multi-drug resistant Gram-negative pathogens of highest critical priority and summarizes the current state-of-the-art in phage therapy targeting these organisms. It also examines phage therapy in humans in general and the approaches different countries have taken to introduce it into clinical practice and policy. We aim to highlight the rapidly advancing field of phage therapy and the challenges that lie ahead as the world shifts away from complete reliance on antibiotics.

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The N-terminal and central domain of colicin A enables phage lysin to lyse Escherichia coli extracellularly

Cited by 37 publications

References 35 publications

Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria

Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria

Gram-Negative Bacterial Lysins

Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles

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