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Human metallo-?-lactamase enzymes degrade penicillin.

ABSTRACT: Nonribosomal peptides are assemblages, including antibiotics, of canonical amino acids and other molecules. ?-lactam antibiotics act on bacterial cell walls and can be cleaved by ?-lactamases. ?-lactamase activity in humans has been neglected, even though eighteen enzymes have already been annotated such in human genome. Their hydrolysis activities on antibiotics have not been previously investigated. Here, we report that human cells were able to digest penicillin and this activity was inhibited by ?-lactamase inhibitor, i.e. sulbactam. Penicillin degradation in human cells was microbiologically demonstrated on Pneumococcus. We expressed a MBLAC2 human ?-lactamase, known as an exosome biogenesis enzyme. It cleaved penicillin and was inhibited by sulbactam. Finally, ?-lactamases are widely distributed, archaic, and have wide spectrum, including digesting anticancer and ?-lactams, that can be then used as nutriments. The evidence of the other MBLAC2 role as a bona fide ?-lactamase allows for reassessment of ?-lactams and ?-lactamases role in humans.

SUBMITTER: Diene SM

PROVIDER: S-EPMC6704141 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Human metallo-β-lactamase enzymes degrade penicillin.

Diene Seydina M SM Pinault Lucile L Keshri Vivek V Armstrong Nicholas N Khelaifia Saber S Chabrière Eric E Caetano-Anolles Gustavo G Colson Philippe P La Scola Bernard B Rolain Jean-Marc JM Pontarotti Pierre P Raoult Didier D

Scientific reports 20190821 1

Nonribosomal peptides are assemblages, including antibiotics, of canonical amino acids and other molecules. β-lactam antibiotics act on bacterial cell walls and can be cleaved by β-lactamases. β-lactamase activity in humans has been neglected, even though eighteen enzymes have already been annotated such in human genome. Their hydrolysis activities on antibiotics have not been previously investigated. Here, we report that human cells were able to digest penicillin and this activity was inhibited ...[more]

PMID: 31434986

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Project description:Metallo-?-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-?-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available ?-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??M, and its inactivation constant (K inact), which was 0.0406 min-1, demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor.IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported to be critical in the World Health Organization's priority pathogens list for the research and development of new antibiotics. CRE produce enzymes, such as metallo-?-lactamases (MBLs), which inactivate ?-lactam antibiotics. Combination therapies involving a ?-lactam antibiotic and a ?-lactamase inhibitor remain a major treatment option for infections caused by ?-lactamase-producing organisms. Currently, no MBL inhibitor-?-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the activity of carbapenem. This study demonstrates that TACN inhibits MBLs efficiently and holds promises as a potential MBL inhibitor to help curb the global health threat posed by MBL-producing CREs.

Dataset Information

Human metallo-?-lactamase enzymes degrade penicillin.

Publications

Human metallo-β-lactamase enzymes degrade penicillin.

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