期刊
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
卷 71, 期 10, 页码 2767-2781出版社
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkw222
关键词
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资金
- BBSRC CASE PhD studentship
- Pfizer
- Imperial NIHR BRC Confidence in Concepts Grant
- MRC (MRC Centre Grant) [G1000758]
- Asthma UK Chair [CH11SJ]
- Imperial College London
- MRC-DTP award
- MRC [MR/L012693/1, G1100238] Funding Source: UKRI
- Asthma UK [CH11SJ] Funding Source: researchfish
- Medical Research Council [MR/L012693/1, G1100238] Funding Source: researchfish
Background: Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity. Methods: In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined. Results: The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC(50)aEuroS=aEuroS5-11 mu M) of rhinovirus-induced type I IFN beta, type III IFN lambda 1 and type III IFN lambda 2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities. Conclusions: The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with anti-inflammatory, antibacterial and antiviral activity and show surprising versatility depending on the clinical need.
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