TY - JOUR
T1 - The Azithromycin Pro-Drug CSY5669 Boosts Bacterial Killing While Attenuating Lung Inflammation Associated with Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus
AU - Saris, Anno
AU - Qin, Wanhai
AU - van Linge, Christine C. A.
AU - Reijnders, Tom D. Y.
AU - Florquin, Sandrine
AU - Burnet, Michael
AU - Strass, Simon
AU - de Vos, Alex F.
AU - van der Poll, Tom
N1 - Funding Information: The authors would like give special thanks to Marieke 10 Brink, who conducted all of the animal studies. Furthermore, we thank Jacky van der Leeuw and Regina de Beer for their help with laboratory work, all involved employees from Synovo for helping to produce the necessary compounds, and especially Jamil Guezguez for measuring pharmacokinetic and pharmacodynamic data. This work was supported by the research program NACTAR (Novel Antibiotic Compounds and Therapies Antagonizing Resistance; grant number 16447), which is financed by the Dutch Research Council (Nederlandse Organisatie voor Wetenschappelijk Onderzoek [NWO]). Funders were not involved in the study design or in the writing of the manuscript in any way. Publisher Copyright: © 2022 Saris et al.
PY - 2022/9/20
Y1 - 2022/9/20
N2 - 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% 6 20% in monocyte-derived macrophages and by 55% 6 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 mmol/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.
AB - 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% 6 20% in monocyte-derived macrophages and by 55% 6 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 mmol/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.
KW - MRSA
KW - Staphylococcus aureus
KW - drug resistance
KW - host directed therapies
KW - host-pathogen interactions
KW - immune response
UR - http://www.scopus.com/inward/record.url?scp=85138459688&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/aac.02298-21
DO - https://doi.org/10.1128/aac.02298-21
M3 - Article
C2 - 35972289
SN - 0066-4804
VL - 66
SP - e0229821
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 9
ER -