Novel antibody–antibiotic conjugate eliminates intracellular S. aureus

  title={Novel antibody–antibiotic conjugate eliminates intracellular S. aureus},
  author={Sophie M. Lehar and Thomas H. Pillow and Min Xu and Leanna R. Staben and Kimberly K. Kajihara and Richard Vandlen and Laura DePalatis and Helga Raab and Wouter L. W. Hazenbos and J. Hiroshi Morisaki and Janice Kim and Summer Park and Martine Darwish and Byoung-Chul Lee and Hilda Hernandez and Kelly M Loyet and Patrick J. Lupardus and Rina Fong and Donghong Yan and Cécile Chalouni and Elizabeth Luis and Yana Khalfin and Emile G. Plise and Jonathan Cheong and Joseph Peter Lyssikatos and Magnus Strandh and Klaus Koefoed and Peter Sejer Andersen and Johan Flygare and Man-Wah Tan and Eric J. Brown and Sanjeev Mariathasan},
Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel… 
Antibacterial drugs: Antibody–antibiotic conjugate tracks down hidden S. aureus
  • N. Bray
  • Biology
    Nature Reviews Drug Discovery
  • 2015
targeting intracellular S. aureus — for example with this AAC — may be a clinically relevant and effective way of preventing colonization and reducing the risk of developing chronic infections.
Intracellular Habitation of Staphylococcus aureus: Molecular Mechanisms and Prospects for Antimicrobial Therapy
This review describes the different intracellular aspects of MRSA infection and briefly mention S. aureus evasion strategies, and discusses how this intrACEllular niche of bacteria may assist in antibiotic tolerance development, and describes various new antibacterial strategies that target the intrace cellular niche.
Potent Killing of Pseudomonas aeruginosa by an Antibody-Antibiotic Conjugate
Pseudomonas aeruginosa infections is associated with low clinical success, despite the availability of antibiotics that are active in standard microbiological in vitro assays, affirming the need for new therapeutic approaches.
Antibody-Based Agents in the Management of Antibiotic-Resistant Staphylococcus aureus Diseases
An update on efforts to develop antibody-based agents, particularly monoclonal antibodies, and their therapeutic potential in the passive immunization approach to the treatment and prevention of S. aureus infections is reported.
Overcoming Planktonic and Intracellular Staphylococcus aureus-Associated Infection with a Cell-Penetrating Peptide-Conjugated Antimicrobial Peptide.
The results suggest that the novel antimicrobial TAT-KR-12 may prove to be an effective treatment option to overcome antibiotic resistance caused by intracellular bacterial infections.
Host-Targeted Therapeutics against Multidrug Resistant Intracellular Staphylococcus aureus
The exploitation of host-directed approaches as a promising strategy going forward for novel anti-infective therapies against S. aureus infections is highlighted.
The Role of Macrophages in Staphylococcus aureus Infection
Staphylococcus aureus is a member of the human commensal microflora that exists, apparently benignly, at multiple sites on the host. However, as an opportunist pathogen it can also cause a range of
Antibiotics: Homed to the hideout
A single dose of AAC is effective in a mouse model of bacteraemia, and is superior to the use of vancomycin, the current standard of care for MRSA infection.
Targeting Hidden Pathogens: Cell-Penetrating Enzybiotics Eradicate Intracellular Drug-Resistant Staphylococcus aureus
The increasing prevalence of antibiotic-resistant bacteria is one of the most urgent problems of our time. Staphylococcus aureus is an important human pathogen that has acquired several mechanisms to


Survival of Staphylococcus aureus Inside Neutrophils Contributes to Infection1
It is shown that PMN isolated from the site of infection contain viable intracellular organisms and that these infected PMN are sufficient to establish infection in a naive animal and that modulation of the inflammatory response is sufficient to significantly alter morbidity and mortality induced by S. aureus infection.
Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus?
It is proposed that phagocytes, and specifically neutrophils, represent a privileged site for S. aureus in the bloodstream, offering protection from most antibiotics and providing a mechanism by which the bacterium can travel to and infect distant sites.
Intracellular Activity of Antibiotics against Staphylococcus aureus in a Mouse Peritonitis Model
A poor correlation between the intracellular accumulation of the antibiotics and the actual intrACEllular effect was found and stresses the importance of performing experimental studies, like those with the new in vivo model described here, to measure actual intrace cellular activity instead of making predictions based on cellular pharmacokinetic and MICs.
Intracellular staphylococcus aureus: Live-in and let die
The focus of this review is to present a guide to recent research outlining the variety of intracellular fates of S. aureus.
Return of the Trojan horse: intracellular phenotype switching and immune evasion by Staphylococcus aureus
Findings presented in this issue of EMBO Molecular Medicine are highlighted, who present strong evidence that SCVs can arise in chronic infection models when S. aureus is internalized in non‐professional phagocytes and survives intracellularly.
Evidence of an intracellular reservoir in the nasal mucosa of patients with recurrent Staphylococcus aureus rhinosinusitis.
Heavily infected foci of intracellular bacteria located in nasal epithelium, glandular, and myofibroblastic cells were revealed by inverted confocal laser scan fluorescence and electron microscopic examination of posttherapy intranasal biopsy specimens from symptom-free patients undergoing surgery on the sinuses.
Gentamicin antibacterial activity in the presence of human polymorphonuclear leukocytes
Results show that intraleukocytic S. aureus are protected from the bactericidal action of gentamicin and suggest that this protection can be explained by poor intracellular penetration of the antibiotic.
The expression of alpha‐haemolysin is required for Staphylococcus aureus phagosomal escape after internalization in CFT‐1 cells
It is shown that an agr mutant of S. aureus strain RN6390 was unable to escape from the endocytic vesicle after invasion of the CFT‐1 cells using markers of vesicular trafficking (LAMP‐1 and 2, LysoTracker and Vacuolar‐ATPase).
Phagocytosis of Staphylococcus aureus by Human Neutrophils Prevents Macrophage Efferocytosis and Induces Programmed Necrosis
These data are the first demonstration, to the authors' knowledge, that bacteria can promote sustained expression of proliferating cell nuclear Ag and that human PMN undergo necroptosis, and demonstrate that S. aureus surviving within PMN undermine the innate immune response and may provide insight into the pathogenesis of S.aureus disease.
Rapid Neutrophil Destruction following Phagocytosis of Staphylococcus aureus
The data suggest that neutrophil destruction after phagocytosis of USA300 is in part a form of programmed necrosis rather than direct lysis by S. aureus pore-forming toxins.