Disarming <i>Staphylococcus aureus</i> from destroying human cells by simultaneously neutralizing six cytotoxins with two human monoclonal antibodies

Rouha, Harald; Weber, Susanne; Janesch, Philipp; Maierhofer, Barbara; Groß, Karin; Dolezilkova, Ivana; Mirkina, Irina; Visram, Zehra; Malafa, Stefan; Stulik, Lukas; Badarau, Adriana; Nagy, Eszter

doi:10.1080/21505594.2017.1391447

Cited by 35 publications

(41 citation statements)

References 62 publications

(53 reference statements)

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“…These data highlight several drawbacks to the single-target approach for opsonic monoclonal antibodies against S. aureus. Some therapeutic antibodies now in clinical trials, such as MEDI4893 and ASN100, focus on neutralization of staphylococcal toxins and have shown promising results in certain infection settings, such as that of staphylococcal pneumonia, where such toxins are particularly important (51,52). Nevertheless, devel-…”

Section: Discussionmentioning

confidence: 99%

Lysostaphin Lysibody Leads to Effective Opsonization and Killing of Methicillin-Resistant Staphylococcus aureus in a Murine Model

Raz

Serrano

Thaker

et al. 2018

Antimicrob Agents Chemother

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The cell wall of Gram-positive bacteria contains abundant surface-exposed carbohydrate structures that are highly conserved. While these properties make surface carbohydrates ideal targets for immunotherapy, carbohydrates elicit a poor immune response that results primarily in low-affinity IgM antibodies. In a previous publication, we introduced the lysibody approach to address this shortcoming. Lysibodies are engineered molecules that combine a high-affinity carbohydrate-binding domain of bacterial or bacteriophage origin and an Fc effector portion of a human IgG antibody, thus directing effective immunity to conserved bacterial surface carbohydrates. Here, we describe the first example of a lysibody containing the binding domain from a bacteriocin, lysostaphin. We also describe the creation of five lysibodies with binding domains derived from phage lysins, directed against The lysostaphin and LysK lysibodies showed the most promise and were further characterized. Both lysibodies bound a range of clinically important staphylococcal strains, fixed complement on the staphylococcal surface, and induced phagocytosis of by macrophages and human neutrophils. The lysostaphin lysibody had superior activity compared to that of the LysK lysibody, as well as that of the previously characterized ClyS lysibody, and it effectively protected mice in a kidney abscess/bacteremia model. These results further demonstrate that the lysibody approach is a reproducible means of creating antibacterial antibodies that cannot be produced by conventional means. Lysibodies therefore are a promising solution for opsonic antibodies that may be used passively to both treat and prevent infection by drug-resistant pathogens.

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Section: Discussionmentioning

confidence: 99%

Lysostaphin Lysibody Leads to Effective Opsonization and Killing of Methicillin-Resistant Staphylococcus aureus in a Murine Model

Raz

Serrano

Thaker

et al. 2018

Antimicrob Agents Chemother

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“…ASN-100, previously developed by Arsanis Inc. (now X4 Pharmaceuticals) is an investigational monoclonal antibody, involving a combination of two co-administered human monoclonal antibodies, ASN-1 and ASN-2 [238]. ASN-100 neutralises six cytotoxins released by S. aureus: α-haemolysin, H1gAB, H1gCB, LukED, LukSF and LukGH leucocidins, which inhibit the cytolytic activity of S. aureus towards human cells in vitro [238].…”

Section: Asn-100mentioning

confidence: 99%

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

Koulenti

Song

et al. 2020

Microorganisms

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Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

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“…LukGH is expressed in human infections and appears to be the most potent S. aureus leukocidin based on in vitro and ex vivo data (22)(23)(24)(25). It is however inactive or displays limited activity in the established S. aureus in vivo models, such as mouse and rabbit, which hinders the study of its role in S. aureus pathogenesis (7,26).…”

Section: Significancementioning

confidence: 99%

“…Cytotoxicity Assay. Cell-based assays were performed using either differentiated HL-60 cells or human, rabbit, or mouse PMNs, and cytolytic activity of LukGH (wild-type and variants) was assessed as described previously (24,25), as detailed in SI Appendix, Supplementary Material and Methods. Cell viability was determined with a Cell Titer-Glo Luminescent Cell Viability Assay Kit (Promega) according to the manufacturer's instructions.…”

Section: Purification Of Lukgh-hucd11b-i-fab and Lukgh-fab Complexes mentioning

confidence: 99%

Molecular mechanism of leukocidin GH–integrin CD11b/CD18 recognition and species specificity

Trstenjak

Milić

Graewert

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Host–pathogen interactions are central to understanding microbial pathogenesis. The staphylococcal pore-forming cytotoxins hijack important immune molecules but little is known about the underlying molecular mechanisms of cytotoxin–receptor interaction and host specificity. Here we report the structures of a staphylococcal pore-forming cytotoxin, leukocidin GH (LukGH), in complex with its receptor (the α-I domain of complement receptor 3, CD11b-I), both for the human and murine homologs. We observe 2 binding interfaces, on the LukG and the LukH protomers, and show that human CD11b-I induces LukGH oligomerization in solution. LukGH binds murine CD11b-I weakly and is inactive toward murine neutrophils. Using a LukGH variant engineered to bind mouse CD11b-I, we demonstrate that cytolytic activity does not only require binding but also receptor-dependent oligomerization. Our studies provide an unprecedented insight into bicomponent leukocidin–host receptor interaction, enabling the development of antitoxin approaches and improved animal models to explore these approaches.

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Disarming Staphylococcus aureus from destroying human cells by simultaneously neutralizing six cytotoxins with two human monoclonal antibodies

Cited by 35 publications

References 62 publications

Lysostaphin Lysibody Leads to Effective Opsonization and Killing of Methicillin-Resistant Staphylococcus aureus in a Murine Model

Lysostaphin Lysibody Leads to Effective Opsonization and Killing of Methicillin-Resistant Staphylococcus aureus in a Murine Model

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

Molecular mechanism of leukocidin GH–integrin CD11b/CD18 recognition and species specificity

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