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The Azithromycin Pro-Drug CSY5669 Boosts Bacterial Killing While Attenuating Lung Inflammation Associated with
Anno Saris1,2, Wanhai Qin1, Christine C A van Linge1
1Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Centergrid.5650.6, University of Amsterdam, Amsterdam, the Netherlands.
Abstract:
Antibiotic resistance is a major problem, with methicillin-resistant Staphylococcus aureus (MRSA) being a prototypical example in surgical and community-acquired infections. S. aureus, like many pathogens, is immune evasive and able to multiply within host immune cells. Consequently, compounds that aid host immunity (e.g., by stimulating the host-mediated killing of pathogens) are appealing alternatives or adjuncts to classical antibiotics. Azithromycin is both an antibacterial and an immunomodulatory drug that accumulates in immune cells. We set out to improve the immunomodulatory properties of azithromycin by coupling the immune activators, nitric oxide and acetate, to its core structure. This new compound, designated CSY5669, enhanced the intracellular killing of MRSA by 45% ± 20% in monocyte-derived macrophages and by 55% ± 15% in peripheral blood leukocytes, compared with untreated controls. CSY5669-treated peripheral blood leukocytes produced fewer proinflammatory cytokines, while in both monocyte-derived macrophages and peripheral blood leukocytes, phagocytosis, ROS production, and degranulation were unaffected. In mice with MRSA pneumonia, CSY5669 treatment reduced inflammation, lung pathology and vascular leakage with doses as low as 0.01 μmol/kg p.o. CSY5669 had diminished direct in vitro antibacterial properties compared with azithromycin. Also, CSY5669 was immunomodulatory at concentrations well below 1% of the minimum inhibitory concentration, which would minimize selection for macrolide-resistant bacteria if it were to be used as a host-directed therapy. This study highlights the potential of CSY5669 as a possible adjunctive therapy in pneumonia caused by MRSA, as CSY5669 could enhance bacterial eradication while simultaneously limiting inflammation-associated pathology.
Insights
A novel compound, CSY5669, enhances immune cell killing of methicillin-resistant Staphylococcus aureus (MRSA) and reduces inflammation in pneumonia models. This host-directed therapy offers a potential alternative to traditional antibiotics for combating MRSA infections.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Antibiotic resistance, exemplified by methicillin-resistant Staphylococcus aureus (MRSA), poses a significant global health threat.
- Pathogens like S. aureus evade host immunity, necessitating novel therapeutic strategies beyond conventional antibiotics.
- Azithromycin exhibits both antibacterial and immunomodulatory effects, accumulating in immune cells.
Purpose of the Study:
- To enhance the immunomodulatory properties of azithromycin by synthesizing a novel compound, CSY5669, by coupling nitric oxide and acetate.
- To evaluate the efficacy of CSY5669 in enhancing host-mediated killing of MRSA and reducing inflammation.
- To assess the safety profile of CSY5669 concerning direct antibacterial activity and potential for resistance development.
Main Methods:
- CSY5669 was synthesized by chemically modifying azithromycin.
- In vitro assays were performed using monocyte-derived macrophages and peripheral blood leukocytes to assess MRSA killing, cytokine production, phagocytosis, and reactive oxygen species (ROS) generation.
- In vivo efficacy was evaluated in a mouse model of MRSA pneumonia, assessing inflammation, lung pathology, and vascular leakage.
Main Results:
- CSY5669 significantly enhanced intracellular MRSA killing in human immune cells (45-55% increase).
- CSY5669 treatment led to reduced pro-inflammatory cytokine production and decreased inflammation, lung pathology, and vascular leakage in a mouse MRSA pneumonia model.
- CSY5669 demonstrated diminished direct in vitro antibacterial activity compared to azithromycin and was immunomodulatory at sub-inhibitory concentrations, suggesting a lower risk of resistance selection.
Conclusions:
- CSY5669 shows promise as a host-directed therapy for MRSA infections, particularly pneumonia.
- The compound enhances bacterial eradication by boosting host immunity while mitigating detrimental inflammation.
- CSY5669 represents a potential adjunctive strategy to combat antibiotic-resistant pathogens with a reduced risk of driving further resistance.
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