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Tytuł pozycji:

Identification of novel targets of azithromycin activity against Pseudomonas aeruginosa grown in physiologically relevant media.

Tytuł:
Identification of novel targets of azithromycin activity against Pseudomonas aeruginosa grown in physiologically relevant media.
Autorzy:
Belanger CR; Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
Lee AH; Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
Pletzer D; Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.; Department of Microbiology and Immunology, University of Otago, 4GP7+94 Dunedin, New Zealand.
Dhillon BK; Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
Falsafi R; Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
Hancock REW; Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4; .
Źródło:
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Dec 29; Vol. 117 (52), pp. 33519-33529. Date of Electronic Publication: 2020 Dec 14.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms:
Azithromycin/*pharmacology
Culture Media/*pharmacology
Pseudomonas aeruginosa/*growth & development
Anti-Bacterial Agents/pharmacology ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Drug Synergism ; Gene Expression Regulation, Bacterial/drug effects ; Humans ; Macrolides/pharmacology ; Microbial Sensitivity Tests ; Operon/genetics ; Peptides/pharmacology ; Pseudomonas aeruginosa/drug effects ; Pseudomonas aeruginosa/genetics ; Serum
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Grant Information:
FDN-154287 Canada CIHR
Contributed Indexing:
Keywords: Pseudomonas aeruginosa; RNA-Seq; antibiotic susceptibility; azithromycin; host-mimicking media
Substance Nomenclature:
0 (Anti-Bacterial Agents)
0 (Culture Media)
0 (Macrolides)
0 (Peptides)
83905-01-5 (Azithromycin)
Entry Date(s):
Date Created: 20201215 Date Completed: 20210210 Latest Revision: 20210615
Update Code:
20240104
PubMed Central ID:
PMC7777150
DOI:
10.1073/pnas.2007626117
PMID:
33318204
Czasopismo naukowe
Pseudomonas aeruginosa causes severe multidrug-resistant infections that often lead to bacteremia and sepsis. Physiologically relevant conditions can increase the susceptibility of pathogens to antibiotics, such as azithromycin (AZM). When compared to minimal-inhibitory concentrations (MICs) in laboratory media, AZM had a 16-fold lower MIC in tissue culture medium with 5% Mueller Hinton broth (MHB) and a 64-fold lower MIC in this tissue culture medium with 20% human serum. AZM also demonstrated increased synergy in combination with synthetic host-defense peptides DJK-5 and IDR-1018 under host-like conditions and in a murine abscess model. To mechanistically study the altered effects of AZM under physiologically relevant conditions, global transcriptional analysis was performed on P. aeruginosa with and without effective concentrations of AZM. This revealed that the arn operon, mediating arabinosaminylation of lipopolysaccharides and related regulatory systems, was down-regulated in host-like media when compared to MHB. Inactivation of genes within the arn operon led to increased susceptibility of P. aeruginosa to AZM and great increases in synergy between AZM and other antimicrobial agents, indicating that dysregulation of the arn operon might explain increased AZM uptake and synergy in host-like media. Furthermore, genes involved in central and energy metabolism and ribosome biogenesis were dysregulated more in physiologically relevant conditions treated with AZM, likely due to general changes in cell physiology as a result of the increased effectiveness of AZM in these conditions. These data suggest that, in addition to the arn operon, there are multiple factors in host-like environments that are responsible for observed changes in susceptibility.
Competing Interests: The authors declare no competing interest.

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