1,4,7-Triazacyclononane restores the activity of β-lactam antibiotics against metallo-β-lactamase-producing Enterobacteriaceae : exploration of potential metallo-β-lactamase inhibitors

dc.contributor.authorSomboro, Anou M.
dc.contributor.authorAmoako, Daniel G.
dc.contributor.authorOsei Sekyere, John
dc.contributor.authorKumalo, Hezekiel M.
dc.contributor.authorKhan, René
dc.contributor.authorBester, Linda A.
dc.contributor.authorEssack, Sabiha Y.
dc.date.accessioned2019-02-05T11:41:51Z
dc.date.issued2019-02
dc.description.abstractMetallo-β-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-β-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available β-lactams are thus imperative. We investigated a zinc-chelating moiety, 1,4,7-triazacyclononane (TACN), for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae. MICs, minimum bactericidal concentrations (MBCs), the serum effect, fractional inhibitory concentration indexes, and time-kill kinetics were determined using broth microdilution techniques according to Clinical and Laboratory Standards Institute (CSLI) guidelines. Enzyme kinetic parameters and the cytotoxic effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from between 8 and 64 mg/liter to 0.03 mg/liter in the presence of TACN. The TACN-meropenem combination showed bactericidal effects with an MBC/MIC ratio of ≤4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be noncytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active-site pockets. This was supported by its inhibition constant (Ki), which was 0.044 μM, and its inactivation constant (Kinact), which was 0.0406 min−1, demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor.en_ZA
dc.description.departmentMedical Microbiologyen_ZA
dc.description.embargo2019-08-01
dc.description.librarianhj2019en_ZA
dc.description.sponsorshipThe South African National Research Foundation (grant no. 85595 awarded to S. Y. Essack as incentive funding for rated researchers) and the College of Health Sciences, University of Kwa-Zulu Natal.en_ZA
dc.description.urihttp://aem.asm.orgen_ZA
dc.identifier.citationSomboro AM, Amoako DG, Osei Sekyere J, Kumalo HM, Khan R, Bester LA, Essack SY. 2019. 1,4,7-Triazacyclononane restores the activity of β-lactam antibiotics against metallo-β-lactamase-producing Enterobacteriaceae: exploration of potential metallo-β-lactamase inhibitors. Appl Environ Microbiol 85:e02077-18. https://doi.org/10 .1128/AEM.02077-18.en_ZA
dc.identifier.issn0099-2240 (print)
dc.identifier.issn1098-5336 (online)
dc.identifier.other10.1128/AEM.02077-18
dc.identifier.urihttp://hdl.handle.net/2263/68409
dc.language.isoenen_ZA
dc.publisherAmerican Society for Microbiologyen_ZA
dc.rights© 2019 American Society for Microbiology. All Rights Reserved.en_ZA
dc.subjectMetallo-β-lactamase (MBL)en_ZA
dc.subjectMinimum bactericidal concentration (MBC)en_ZA
dc.subject1,4,7-triazacyclononane (TACN)en_ZA
dc.subjectBinding affinityen_ZA
dc.subjectEnterobacteriaceaeen_ZA
dc.subjectβ-lactamsen_ZA
dc.title1,4,7-Triazacyclononane restores the activity of β-lactam antibiotics against metallo-β-lactamase-producing Enterobacteriaceae : exploration of potential metallo-β-lactamase inhibitorsen_ZA
dc.typePostprint Articleen_ZA

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