Alanine Scanning Mutagenesis of the MEDI4893 (Suvratoxumab) Epitope Reduces Alpha Toxin Lytic Activity
            <i>In Vitro</i>
            and Staphylococcus aureus Fitness in Infection Models

Tkaczyk, Christine; Семенова, Е. А.; Shi, Yueyue; Rosenthal, Kim; Oganesyan, Vaheh; Warrener, Paul; Stover, Charles K; Sellman, Bret R.

doi:10.1128/aac.01033-18

Cited by 18 publications

(16 citation statements)

References 37 publications

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“…Targeting individual virulence mechanisms, such as PFTs, may have more limited risk of resistance compared to regulatory targets like agr that have the potential to impact large sets of virulence factors. Moreover, S. aureus mutants with emergent resistance to some antivirulence treatments may exhibit reduced overall fitness, as has been observed with mutants resistant to MEDI4893 ( Tkaczyk et al, 2018 ). Targeting individual PFTs in S. aureus may lack efficacy due to functional redundancy of cytolytic toxins.…”

Section: Discussionmentioning

confidence: 92%

“…Alanine scanning of this highly conserved region identified S. aureus mutants resistant to MEDI4893 neutralization. Importantly, mutants resistant to neutralization show reduced dermatonecrosis and mortality in murine models of S. aureus skin infection and pneumonia, respectively, likely reflecting impaired Hla function in the mutants ( Tkaczyk et al, 2018 ). As of November 2020, MEDI4893 has completed Phase 2 clinical trials for prevention of S. aureus pneumonia in high-risk ICU patients.…”

Section: Antivirulence Strategiesmentioning

confidence: 99%

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Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

2021

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Staphylococcus aureus is a Gram-positive bacterium capable of infecting nearly all host tissues, causing severe morbidity and mortality. Widespread antimicrobial resistance has emerged among S. aureus clinical isolates, which are now the most frequent causes of nosocomial infection among drug-resistant pathogens. S. aureus produces an array of virulence factors that enhance in vivo fitness by liberating nutrients from the host or evading host immune responses. Staphylococcal virulence factors have been identified as viable therapeutic targets for treatment, as they contribute to disease pathogenesis, tissue injury, and treatment failure. Antivirulence strategies, or treatments targeting virulence without direct toxicity to the inciting pathogen, show promise as an adjunctive therapy to traditional antimicrobials. This Mini Review examines recent research on S. aureus antivirulence strategies, with an emphasis on translational studies. While many different virulence factors have been investigated as therapeutic targets, this review focuses on strategies targeting three virulence categories: pore-forming toxins, immune evasion mechanisms, and the S. aureus quorum sensing system. These major areas of S. aureus antivirulence research demonstrate broad principles that may apply to other human pathogens. Finally, challenges of antivirulence research are outlined including the potential for resistance, the need to investigate multiple infection models, and the importance of studying antivirulence in conjunction with traditional antimicrobial treatments.

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Section: Discussionmentioning

confidence: 92%

Section: Antivirulence Strategiesmentioning

confidence: 99%

Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

2021

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“…However, because antibodies often target virulence factors and not proteins required for survival, a mutation of these targets is likely to make bacteria non-virulent or less virulent, possibly subject to enhanced immune system clearance. A recent study supported this idea and showed that when the alpha-toxin epitope for MEDI4839 was mutagenized, S. aureus had a reduced fitness cost [72]. Another criticism of this approach is the narrow spectrum of the products, as they largely only target one bacterial species; however, this limitation has been somewhat overcome with the use of onboard diagnostics with clinical trials, where a complement diagnostic antibody or PCR test is used to identify patients infected with a particular bacterial species upfront before treatment.…”

Section: Future and Conclusionmentioning

confidence: 93%

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

2020

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In the beginning of the 21st century, the frequency of antimicrobial resistance (AMR) has reached an apex, where even 4th and 5th generation antibiotics are becoming useless in clinical settings. In turn, patients are suffering from once-curable infections, with increases in morbidity and mortality. The root cause of many of these infections are the ESKAPEE pathogens (Enterococcus species, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli), which thrive in the nosocomial environment and are the bacterial species that have seen the largest rise in the acquisition of antibiotic resistance genes. While traditional small-molecule development still dominates the antibacterial landscape for solutions to AMR, some researchers are now turning to biological approaches as potential game changers. Monoclonal antibodies (mAbs)—more specifically, human monoclonal antibodies (Hu-mAbs)—have been highly pursued in the anti-cancer, autoimmune, and antiviral fields with many success stories, but antibody development for bacterial infection is still just scratching the surface. The untapped potential for Hu-mAbs to be used as a prophylactic or therapeutic treatment for bacterial infection is exciting, as these biologics do not have the same toxicity hurdles of small molecules, could have less resistance as they often target virulence proteins rather than proteins required for survival, and are narrow spectrum (targeting just one pathogenic species), therefore avoiding the disruption of the microbiome. This mini-review will highlight the current antibacterial mAbs approved for patient use, the success stories for mAb development, and new Hu-mAb products in the antibacterial pipeline.

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“…More recently, clinical studies of mAb MEDI4893 [Medimmune, Gaithersburg MD] demonstrate it to reach levels in the blood and nares capable of neutralizing S. aureus alphahemolysin to prevent invasion (14). Thanks to the high conservation of the alpha-hemolysin (15), the therapy is likely immune to resistance, but its inability to alter S. aureus colonization or bacterial expression may limit it use to prophylaxis (14). Thus, while antitoxin mAbs seem effective as preventative strategies or as adjunctive treatments to improve antibiotic success (7), their ability to directly treat acute disease may be limited.…”

Section: Antibodies Against Bacterial Toxinsmentioning

confidence: 99%

Monoclonal antibody-based therapies for bacterial infections

Motley

Banerjee

Fries

2019

Current Opinion in Infectious Diseases

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Purpose of review-This review highlights recent developments in the development of monoclonal antibodies to treat bacterial disease, including preclinical advances and the status of current clinical trials. Recent Findings-Monoclonal antibody (mAb) therapy is becoming increasingly promising in the infectious disease field. Though bacterial exotoxins continue to be a mainstay of mAb targets, searches for protein targets on the surface of bacteria have uncovered new mechanisms of antibody-mediated action against bacteria. Additionally, surveys of the polysaccharide serotype prevalence among antibiotic resistant bacterial populations have yielded opportunities to leverage human selective pressures to our clinical advantage. Several mAb candidates are progressing through clinical development with great promise, especially those with structures altered to provide maximum benefit. While other clinical trials have recently proved unsuccessful, these failures and lessons from immune profiling provide opportunities to understand how vulnerabilities of certain targets may change in different disease states. Summary-Despite the hurdles of identifying effective targets and understanding how mAbs provide protection within different infections, we show that the progress made in these fields is a positive indication of mAbs becoming more widely accepted as the future for treating bacterial infections.

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Alanine Scanning Mutagenesis of the MEDI4893 (Suvratoxumab) Epitope Reduces Alpha Toxin Lytic Activity In Vitro and Staphylococcus aureus Fitness in Infection Models

Cited by 18 publications

References 37 publications

Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

Monoclonal antibody-based therapies for bacterial infections

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