The MraY Inhibitor Muraymycin D2 and Its Derivatives Induce Enlarged Cells in Obligate Intracellular Chlamydia and Wolbachia and Break the Persistence Phenotype in Chlamydia .

Autor: Löckener I; Institute for Pharmaceutical Microbiology (IPM), University of Bonn, University Hospital Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany., Behrmann LV; Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany., Reuter J; Institute for Pharmaceutical Microbiology (IPM), University of Bonn, University Hospital Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany., Schiefer A; Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany., Klöckner A; Institute for Pharmaceutical Microbiology (IPM), University of Bonn, University Hospital Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany., Krannich S; Institute for Pharmaceutical Microbiology (IPM), University of Bonn, University Hospital Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany., Otten C; Institute for Pharmaceutical Microbiology (IPM), University of Bonn, University Hospital Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany., Mölleken K; Institute for Functional Microbial Genomics, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany., Ichikawa S; Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan., Hoerauf A; Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 53127 Bonn, Germany., Schneider T; Institute for Pharmaceutical Microbiology (IPM), University of Bonn, University Hospital Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany.; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 53127 Bonn, Germany., Pfarr KM; Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 53127 Bonn, Germany., Henrichfreise B; Institute for Pharmaceutical Microbiology (IPM), University of Bonn, University Hospital Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany.
Jazyk: angličtina
Zdroj: Antibiotics (Basel, Switzerland) [Antibiotics (Basel)] 2024 May 04; Vol. 13 (5). Date of Electronic Publication: 2024 May 04.
DOI: 10.3390/antibiotics13050421
Abstrakt: Chlamydial infections and diseases caused by filarial nematodes are global health concerns. However, treatment presents challenges due to treatment failures potentially caused by persisting Chlamydia and long regimens against filarial infections accompanied by low compliance. A new treatment strategy could be the targeting of the reduced peptidoglycan structures involved in cell division in the obligate intracellular bacteria Chlamydia and Wolbachia , the latter being obligate endosymbionts supporting filarial development, growth, and survival. Here, cell culture experiments with C. trachomatis and Wolbachia showed that the nucleoside antibiotics muraymycin and carbacaprazamycin interfere with bacterial cell division and induce enlarged, aberrant cells resembling the penicillin-induced persistence phenotype in Chlamydia. Enzymatic inhibition experiments with purified C. pneumoniae MraY revealed that muraymycin derivatives abolish the synthesis of the peptidoglycan precursor lipid I. Comparative in silico analyses of chlamydial and wolbachial MraY with the corresponding well-characterized enzyme in Aquifex aeolicus revealed a high degree of conservation, providing evidence for a similar mode of inhibition. Muraymycin D2 treatment eradicated persisting non-dividing C. trachomatis cells from an established penicillin-induced persistent infection. This finding indicates that nucleoside antibiotics may have additional properties that can break bacterial persistence.
Databáze: MEDLINE
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