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

Antibiotics (Basel, Switzerland)

Authors: Iris Löckener, Lara Vanessa Behrmann, Jula Reuter, Andrea Schiefer, Anna Klöckner, Sebastian Krannich, Christian Otten, Katja Mölleken, Satoshi Ichikawa, Achim Hoerauf, Tanja Schneider, Kenneth M Pfarr, Beate Henrichfreise

Chlamydial infections and diseases caused by filarial nematodes are global health concerns. However, treatment presents challenges due to treatment failures potentially caused by persisting 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 and , the latter being obligate endosymbionts supporting filarial development, growth, and survival. Here, cell culture experiments with and 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 Enzymatic inhibition experiments with purified 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 revealed a high degree of conservation, providing evidence for a similar mode of inhibition. Muraymycin D2 treatment eradicated persisting non-dividing cells from an established penicillin-induced persistent infection. This finding indicates that nucleoside antibiotics may have additional properties that can break bacterial persistence.

PMID: 38786149

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