The production of metallo-β-lactamases (MBLs) is one of the major mechanisms adopted by bacterial pathogens to resist carbapenems. One promising strategy to overcome MBLs-mediated carbapenems resistance is to develop effective inhibitors. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost-effective approach to fight infections caused by carbapenem resistant pathogens. Here, twelve FDA-approved compounds were screened to neutralize the ability of NDM-1. Among these compounds, dexrazoxane, embelin, candesartan cilexetil (CAN) and nordihydroguaiaretic acid (NDGA) were further demonstrated to inhibit all tested MBLs, and showed an in vitro synergistic bactericidal effect with meropenem against MBLs-producing bacteria. Mechanistic studies revealed that dexrazoxane, embelin and CAN are metal ion chelating agents, while the inhibition of NDM-1 by NDGA involves its direct binding with the active region of NDM-1. Furthermore, dexrazoxane, embelin and CAN and NDGA dramatically rescued the treatment efficacy of meropenem in three infection models. Our observations indicated that dexrazoxane, embelin, CAN and NDGA are promising carbapenem adjuvants against MBLs-positive carbapenem resistant bacterial pathogens.

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Background and purposeThe production of metallo‐β‐lactamases (MBLs) is one of the major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost‐effective approach to fight infections caused by carbapenem resistant pathogens.Experimental approachThe nitrocefin hydrolysis assay was employed to screen potential NDM‐1 inhibitors from a commercially available U.S. Food and Drug Administration (FDA) ‐approved drug library. The mechanism of inhibition was clarified by metal restoration, inductively coupled plasma mass spectrometry (ICP‐MS) and molecular dynamics simulation. The in vitro synergistic antibacterial effect of the identified inhibitors with meropenem was determined by the checkerboard minimum inhibitory concentration (MIC) assay, time‐dependent killing assay and combined disc test. Three mouse infection models were used to further evaluate the in vivo therapeutic efficacy of combined therapy.Key resultsTwelve FDA‐approved compounds were initially screened to neutralize the ability of NDM‐1 to hydrolyse nitrocefin. Among these compounds, dexrazoxane, embelin, candesartan cilexetil (CAN) and nordihydroguaiaretic acid (NDGA) were further demonstrated to inhibit all tested MBLs, and showed an in vitro synergistic bactericidal effect with meropenem against MBLs‐producing bacteria. Dexrazoxane, embelin and CAN are metal ion chelating agents, while the inhibition of NDM‐1 by NDGA involves its direct binding with the active region of NDM‐1. Furthermore, these four drugs dramatically rescued the treatment efficacy of meropenem in three infection models.Conclusions and implicationsOur observations indicated that dexrazoxane, embelin, CAN and NDGA are promising carbapenem adjuvants against MBLs‐positive carbapenem resistant bacterial pathogens.