Synthesis and Biological Evaluation of Muraymycin Analogues Active against Anti-Drug-Resistant Bacteria

Muraymycin analogues with a lipophilic substituent were synthesized using an Ugi four-component assemblage. This approach provides ready access to a range of analogues simply by altering the aldehyde component. The impact of the lipophilic substituent on the antibacterial activity was very large, an...

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Published inACS medicinal chemistry letters Vol. 1; no. 6; pp. 258 - 262
Main Authors Tanino, Tetsuya, Ichikawa, Satoshi, Al-Dabbagh, Bayan, Bouhss, Ahmed, Oyama, Hiroshi, Matsuda, Akira
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 09.09.2010
Subjects
Letter
peptidoglycan
MraY
drug resistance
muraymycin
Antibiotics
Ugi four-component reaction
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Summary:Muraymycin analogues with a lipophilic substituent were synthesized using an Ugi four-component assemblage. This approach provides ready access to a range of analogues simply by altering the aldehyde component. The impact of the lipophilic substituent on the antibacterial activity was very large, and analogues 7b−e and 8b−e exhibited good activity against a range of Gram-positive bacterial pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. This study also showed that the accessory urea-dipeptide motif contributes to MraY inhibitory and antibacterial activity. The knowledge obtained from our structure−activity relationship study of muraymycins provides further direction toward the design of potent MraY inhibitors. This study has set the stage for the generation of novel antibacterial “lead” compounds based on muraymycins.
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We acknowledge the CNRS UMR 8619 (support of B.A.-D. and A.B.).
Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates.
T.T. contributed to the synthesis of muraymycin analogues. B.A.-D. contributed to the MraY inhibitory assay. S.I. was the PI of T.T., made significant writing and editing contributions, and provided significant intellectual input. A.B. was the PI of B.A.-D. and a collaborator of the Matsuda lab and provided significant intellectual input. H.O. contributed to the cytotoxicity assay. A.M. was the main PI of the entire project, was the overseeing PI of T.T., S.I., and A.B., made significant writing and editing contributions, and provided significant intellectual input.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml100057z