In-vitro and in-vivo Activity of ML302F: A Thioenolate Inhibitor of VIM-subfamily Metallo β-lactamses

Betts, JW, Phee, L, Abdul Momin, MHF, Umland, KD, Brem, J, Schofield, CJ and Wareham, DW (2016) In-vitro and in-vivo Activity of ML302F: A Thioenolate Inhibitor of VIM-subfamily Metallo β-lactamses MedChemComm, 7. pp. 190-193.

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Abstract

The thioenol ML302F was recently identified as an inhibitor of class B metallo-β-lactamases (MBLs). We assessed the activity of ML302F when combined with meropenem (MEM) against 31 carbapenem resistant Gram-negative clinical isolates. Minimum inhibitory concentrations of MEM : ML302F were determined at fixed ratios of 1 : 4 and 1 : 8 using strains producing variants of the clinically relevant VIM-like MBL. Toxicity and efficacy in vivo was assessed in a Galleria mellonella invertebrate model against strains producing VIM-1, VIM-2 and VIM-4 variants. At a fixed MEM : ML302F ratio of 1 : 8, 22/31 isolates were rendered either susceptible (MIC ≤ 2 mg L−1), or intermediate (MIC 4–8 mg L−1) to MEM. ML302F alone was not toxic at up to 80 mg kg−1 in G. mellonella and treatment with MEM 0.6 mg kg−1 : ML302F 4.8 mg kg−1 significantly improved the survival of infected larvae. As ML302F was able to successfully restore susceptibility to resistant strains both in vitro and in vivo it represents a structurally interesting inhibitor in the search for new MBL inhibitors.

Item Type:	Article
Authors :	Name Email ORCID Betts, JW jono.betts@surrey.ac.uk Phee, L Abdul Momin, MHF Umland, KD Brem, J Schofield, CJ Wareham, DW
Date :	10 February 2016
Identification Number :	10.1039/c5md00380f
Depositing User :	Symplectic Elements
Date Deposited :	17 May 2017 10:43
Last Modified :	17 May 2017 14:52
URI:	http://epubs.surrey.ac.uk/id/eprint/828975

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