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

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