A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii

Shajila Siricilla, Katsuhiko Mitachi, Junshu Yang, Shakiba Eslamimehr, Maddie R. Lemieux, Bernd Meibohm, Yinduo Ji, Michio Kurosu

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most difficult Gram-negative bacteria to treat and eradicate. In a cell-based screening of pleuromutilin derivatives against a drug sensitive A. baumannii strain, new molecules (2-4) exhibit bacteriostatic activity with 3.13 μg/mL concentration and 1 shows bactericidal activity with an MBC of 6.25 μg/mL. The pleuromutilin derivative 1 displays strong synergistic effects with doxycycline in a wide range of concentrations. A 35/1 ratio of 1 and doxycycline (1-Dox 35/1) kills drug susceptible A. baumannii with the MBC of 2.0 μg/mL and an MDR A. baumannii with the MBC of 3.13 μg/mL. In vitro anti-Acinetobacter activity of 1-Dox 35/1 is superior to that of clinical drugs such as tobramycin, tigecycline, and colistin. The efficacy of 1-Dox 35/1 is evaluated in a mouse septicemia model; treatment of the infected C57BL/6 mice with 1-Dox 35/1 protects from lethal infection of A. baumannii with an ED50 value of <2.0 mg/kg.

Original languageEnglish (US)
Pages (from-to)2869-2878
Number of pages10
JournalJournal of medicinal chemistry
Volume60
Issue number7
DOIs
StatePublished - Apr 13 2017

Bibliographical note

Funding Information:
The National Institutes of Health is greatly acknowledged for financial support of this work (Grant AI084411). We also thank University of Tennessee for generous financial support (CORNET award). NMR data were obtained on instruments supported by the NIH Shared Instrumentation Grant. The authors gratefully acknowledge Drs. Katsuhisa Yamazaki and Yoshimasa Ishizaki (The Institute of Microbial Chemistry) for useful discussions

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