TY - JOUR
T1 - Fighting Staphylococcus aureus infections with light and photoimmunoconjugates
AU - Bispo, Mafalda
AU - Anaya Sánchez, Andrea
AU - Suhani, Sabrina
AU - Raineri, Elisa
AU - Lopez Alvarez, Marina
AU - Heuker, Marjolein
AU - Szymanski, Wiktor
AU - Romero Pastrana, Francisco
AU - Buist, Girbe
AU - Horswill, Alexander R.
AU - Francis, Kevin P.
AU - Dam, van, Go
AU - Oosten, van, Marleen
AU - Dijl, van, Jan Maarten
PY - 2020/11/19
Y1 - 2020/11/19
N2 - 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.
AB - 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.
KW - Anti-Bacterial Agents/pharmacology
KW - Antibodies, Bacterial/pharmacology
KW - Antibodies, Monoclonal/pharmacology
KW - Antigens, Bacterial/immunology
KW - HeLa Cells
KW - Humans
KW - Photochemotherapy
KW - Photosensitizing Agents/pharmacology
KW - Staphylococcal Infections/microbiology
KW - Staphylococcus aureus/drug effects
U2 - 10.1172/jci. insight.139512
DO - 10.1172/jci. insight.139512
M3 - Article
C2 - 33048846
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 22
M1 - 139512
ER -