Reviving Furosemide as a Metallo-β-Lactamase Inhibitor against MDR Acinetobacter baumannii

Abstract

Carbapenems are considered the last line of antibiotic defense against multidrug-resistant (MDR) Acinetobacter baumannii, a bacterium that can secrete carbapenemases such as metallo-β-lactamases (MBLs) to degrade carbapenems. It is thus critical to develop strategies to combat carbapenem resistance, and one of these strategies is to discover MBL inhibitors. In the current study, we evaluated the possible anti-β-lactamase of the approved safe drug furosemide. Furosemide is a loop diuretic with antihypertensive effects. A clinical MDR and carbapenem-resistant A. baumannii isolate was used. Furosemide at 1 mg/ml potentiated meropenem in the combined disk method and interfered with the hydrolytic activities of MBL. Furthermore, furosemide synergized meropenem and decreased its minimum inhibitory concentration (MIC). Furosemide could also reduce the expression of the MBL genes blaNDM and blaVIM. In silico study showed the binding ability of furosemide with the active sites of New Delhi and VIM MBL enzymes, as well as its chelating interaction with zinc ions. Furosemide is a promising MBL inhibitor that can be used in combination with meropenem to treat infections caused by MBL-producing A. baumannii.