國家衛生研究院 NHRI:Item 3990099045/13010

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Title:	In vitro and in vivo activities of imipenem combined with BLI-489 against class D Beta-lactamase-producing Acinetobacter baumannii
Other Titles:	In vitro and in vivo activities of imipenem combined with BLI-489 against class D β-lactamase-producing Acinetobacter baumannii
Authors:	Wang, YC;Huang, SW;Chiang, MH;Lee, IM;Kuo, SC;Yang, YS;Chiu, CH;Su, YS;Chen, TL;Wang, FD;Lee, YT
Contributors:	National Institute of Infectious Diseases and Vaccinology
Abstract:	BACKGROUND: According to our preliminary study, BLI-489 has the potential to inhibit the hydrolysing activity of OXA-51-like β-lactamase produced by carbapenem-resistant Acinetobacter baumannii (CRAb). OBJECTIVES: In the present study, the in vitro and in vivo activities of imipenem combined with BLI-489 against CRAb producing carbapenem-hydrolysing class D β-lactamases (CHDLs), namely OXA-23, OXA-24, OXA-51 and OXA-58, were determined. METHODS: A chequerboard analysis of imipenem and BLI-489 was performed using 57 and 7 clinical CRAb isolates producing different CHDLs and MBLs, respectively. Four representative strains harbouring different CHDL genes were subjected to a time-kill assay to evaluate the synergistic effects. An in silico docking analysis was conducted to simulate the interactions between BLI-489 and the different families of CHDLs. The in vivo activities of this combination were assessed using a Caenorhabditis elegans survival assay and a mouse pneumonia model. RESULTS: Chequerboard analysis showed that imipenem and BLI-489 had a synergistic effect on 14.3, 92.9, 100, 16.7 and 100% of MBL-, OXA-23-, OXA-24-like-, OXA-51-like- and OXA-58-producing CRAb isolates, respectively. In the time-kill assay, imipenem and BLI-489 showed synergy against OXA-24-like-, OXA-51-like- and OXA-58-, but not OXA-23-producing CRAb isolates after 24 h. The in silico docking analysis showed that BLI-489 could bind to the active sites of OXA-24 and OXA-58 to confer strong inhibition activity. The combination of imipenem and BLI-489 exhibited synergistic effects for the rescue of CRAb-infected C. elegans and mice. CONCLUSIONS: Imipenem combined with BLI-489 has synergistic effects against CHDL-producing CRAb isolates.
Date:	2021-02
Relation:	Journal of Antimicrobial Chemotherapy. 2021 Feb;76(2):451-459.
Link to:	http://dx.doi.org/10.1093/jac/dkaa421
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0305-7453&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000620813200023
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85100280691
Appears in Collections:	[Shu-Chen Kuo] Periodical Articles

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