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Mafalda Bispo1, Andrea Anaya-Sanchez1, Sabrina Suhani1
1Department of Medical Microbiology and.
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.
Insights
Targeted antimicrobial photodynamic therapy (aPDT) using a novel immunoconjugate effectively eradicates methicillin-resistant Staphylococcus aureus (MRSA). This light-activated therapy offers a promising alternative to antibiotics for combating drug-resistant bacterial infections.
Area of Science:
- Microbiology
- Immunology
- Photomedicine
Background:
- Multidrug-resistant Staphylococcus aureus (MRSA) infections pose a significant global health threat, with increasing community-acquired infections.
- Existing antibiotics face limitations due to rising drug resistance, necessitating novel therapeutic strategies.
- Antimicrobial photodynamic therapy (aPDT) presents a promising approach to combat resistant bacteria by utilizing light-activated compounds.
Purpose of the Study:
- To develop and evaluate a targeted aPDT strategy for eradicating MRSA infections.
- To investigate the efficacy of a novel immunoconjugate, 1D9-700DX, for MRSA targeting and photo-inactivation.
- To assess the potential of aPDT in overcoming host-related resistance mechanisms, such as plasma antioxidant properties.
Main Methods:
- Conjugation of a near-infrared photosensitizer (IRDye700DX) to a human monoclonal antibody (mAb) targeting the staphylococcal antigen IsaA, creating the immunoconjugate 1D9-700DX.
- Biochemical characterization of the immunoconjugate.
- Preclinical evaluation of targeted aPDT efficacy in vitro, in vivo, and in a human orthopedic implant infection model.
- Assessment of aPDT performance in the presence of human plasma, with and without potassium iodide as an aPDT-enhancing agent.
Main Results:
- The immunoconjugate 1D9-700DX specifically targets MRSA.
- Targeted aPDT with 1D9-700DX demonstrated high efficacy in eradicating MRSA in various preclinical models.
- The addition of potassium iodide enabled 1D9-700DX to overcome human plasma's antioxidant effects and achieve complete MRSA eradication.
- The therapy effectively killed MRSA upon red light illumination without causing collateral damage to human cells.
Conclusions:
- Targeted antimicrobial photodynamic therapy using the IsaA-targeting immunoconjugate 1D9-700DX is a highly effective strategy against MRSA.
- This novel aPDT approach offers a promising alternative to conventional antibiotics for treating drug-resistant staphylococcal infections.
- The developed therapy shows potential for clinical translation, particularly in challenging infection settings like orthopedic implants.
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