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

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Journal of medicinal chemistry, ISSN: 1520-4804, Vol: 60, Issue: 7, Page: 2869-2878

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Siricilla, Shajila; Mitachi, Katsuhiko; Yang, Junshu; Eslamimehr, Shakiba; Lemieux, Maddie R; Meibohm, Bernd; Ji, Yinduo; Kurosu, Michio
American Chemical Society (ACS)
Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics
article description
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 ED value of <2.0 mg/kg.