Abstract
Infections caused by multidrug-resistant Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), are responsible for high mortality and morbidity worldwide. Resistant lineages were previously confined to hospitals but are now also causing infections among healthy individuals in the community. It is therefore imperative to explore therapeutic avenues that are less prone to raise drug resistance compared with today’s antibiotics. An opportunity to achieve this ambitious goal could be provided by targeted antimicrobial photodynamic therapy (aPDT), which relies on the combination of a bacteria-specific targeting agent and light-induced generation of ROS by an appropriate photosensitizer. Here, we conjugated the near-infrared photosensitizer IRDye700DX to a fully human mAb, specific for the invariantly expressed staphylococcal antigen immunodominant staphylococcal antigen A (IsaA). The resulting immunoconjugate 1D9-700DX was characterized biochemically and in preclinical infection models. As demonstrated in vitro, in vivo, and in a human postmortem orthopedic implant infection model, targeted aPDT with 1D9-700DX is highly effective. Importantly, combined with the nontoxic aPDT-enhancing agent potassium iodide, 1D9-700DX overcomes the antioxidant properties of human plasma and fully eradicates high titers of MRSA. We show that the developed immunoconjugate 1D9-700DX targets MRSA and kills it upon illumination with red light, without causing collateral damage to human cells.
Highlights
Staphylococcus aureus is a Gram-positive bacterium, part of the normal human microbiota, and a leading cause of bacteremia, endocarditis, osteomyelitis, and skin and soft tissue infections [1]
An opportunity to achieve this ambitious goal could be provided by targeted antimicrobial photodynamic therapy, which relies on the combination of a bacteria-specific targeting agent and light-induced generation of ROS by an appropriate photosensitizer
We have previously developed a fully human mAb — 1D9 — which targets the immunodominant staphylococcal antigen A (IsaA), a strictly conserved noncovalently cell wall–bound lytic transglycosylase that is exposed on the surface of all S. aureus isolates tested so far [14,15,16,17,18]. 1D9 was preclinically shown to be highly effective in the noninvasive diagnosis of S. aureus soft tissue infections, as well as spinal and shoulder implant infections in mice using PET-CT or in vivo fluorescence imaging [19,20,21]
Summary
Staphylococcus aureus is a Gram-positive bacterium, part of the normal human microbiota, and a leading cause of bacteremia, endocarditis, osteomyelitis, and skin and soft tissue infections [1]. Such infections are increasingly difficult to treat, partly due to acquired antibiotic resistances, as exemplified by methicillin-resistant S. aureus (MRSA) [2, 3] and partly due to the bacterium’s ability to form thick biofilms on tissues and implanted biomaterials (e.g., catheters, heart valves, and prosthetic joints) [4]. A potential alternative therapeutic approach is antimicrobial photodynamic therapy (aPDT) [6], an emerging treatment modality based on the photoactivation of a photosensitizer with light of an appropriate wavelength.
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