Leucomycin A3, a 16-membered macrolide antibiotic, inhibits influenza A virus infection and disease progression.
Severe respiratory disease arising from influenza virus infection has a high fatality rate. Neutrophil myeloperoxidase (MPO) has been implicated in the pathogenesis of severe influenza-induced pneumonia because extracellularly released MPO mediates the production of hypochlorous acid, a potent tissue injury factor. To search for candidate anti-influenza compounds, we screened leucomycin A3 (LM-A3), spiramycin (SPM), an erythromycin derivative (EM900, in which anti-bacterial activity has been eliminated), and clarithromycin (CAM), by analyzing their ability to inhibit MPO release in neutrophils from mice and humans. When each candidate was injected into mice infected with a lethal dose of A/H1N1 influenza virus (PR-8), LM-A3 produced the highest survival rate (80.9%). We found that LM-A3 induced beneficial effects on lung pathology and viral proliferation involved in the regulatory activity of MPO release, pro-inflammatory cytokines and interferon-α production in the lung. SPM and EM900 also induced positive survival effects in the infected mice, whereas CAM did not. We further found that these compounds inhibit virus proliferation in human pneumonia epithelial A549 cells in vitro. LM-A3 showed effective action against influenza A virus infection with high anti-viral activity in human host cells, indicating the possibility that LM-A3 is a prospective lead compound for the development of a drug for human influenza. The positive survival effect induced by EM900 suggests that pharmacological architectures between anti-bacterial and anti-influenza virus activities can be dissociated in macrolide derivatives. These observations provide valuable evidence for the potential development of novel macrolide derivatives that have strong anti-viral but no anti-bacterial activity.
1] Inflammation Program, Graduate School of Medicine, Chiba University, Chiba City, Japan [2] Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
Ryuichi
R
Sugamata
The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Japan.
Akihiro
A
Sugawara
1] Inflammation Program, Graduate School of Medicine, Chiba University, Chiba City, Japan [2] Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
Tomokazu
T
Nagao
Inflammation Program, Graduate School of Medicine, Chiba University, Chiba City, Japan.
Koya
K
Suzuki
The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Japan.
Tomoyasu
T
Hirose
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
Ki-ichi
K
Yamamoto
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
Masamichi
M
Oshima
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
Kazuo
K
Kobayashi
The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Japan.
Toshiaki
T
Sunazuka
1] Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan [2] The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Japan.
Kiyoko S
KS
Akagawa
The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Japan.
Satoshi
S
Ōmura
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba City, Japan.
Toshinori
T
Nakayama
1] Inflammation Program, Graduate School of Medicine, Chiba University, Chiba City, Japan [2] Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
Kazuo
K
Suzuki
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017291:Clarithromycin / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015195:Drug Design; D004847:Epithelial Cells / Q000821:virology; D004917:Erythromycin / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D015570:Josamycin / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D015572:Spiramycin / Q000494:pharmacology; D015996:Survival Rate
C560918:(8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A; D000998:Antiviral Agents; D016207:Cytokines; D004917:Erythromycin; D015572:Spiramycin; D009195:Peroxidase; D017291:Clarithromycin; D015570:Josamycin