Human metallo-β-lactamase enzymes degrade penicillin

Abstract

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 by β-lactamase inhibitor, i.e. sulbactam. Penicillin degradation in human cells was microbiologically demonstrated on Pneumococcus . We expressed a MBLAC2 human β-lactamase, known as an exosome biogenesis enzyme. It cleaved penicillin and was inhibited by sulbactam. Finally, β-lactamases are widely distributed, archaic, and have wide spectrum, including digesting anticancer and β-lactams, that can be then used as nutriments. The evidence of the other MBLAC2 role as a bona fide β-lactamase allows for reassessment of β-lactams and β-lactamases role in humans.

A metallo-beta-lactamase with both beta-lactamase and ribonuclease activity is linked with traduction in giant viruses

“…Based on the phylogenetic analysis and as MBL folds can hydrolyse nucleic acids 2 , both beta-lactamase and nuclease activities of this purified protein were thereafter tested. We first evaluated the beta-lactamase activity of a pure solution of TupBlac used at a concentration of 1 μg/mL by incubating it with nitrocefin, a chromogenic beta-lactam used to test the beta-lactamase activity 19 . A significant hydrolysis activity was observed ( Fig.…”

“…Beta-lactamases are a priori useless for giant viruses, which are grown in the presence of various antibiotics, including beta-lactams 24 , but our findings enhance the recent reconsideration of the function of MBL fold proteins. Thus, the recent description of penicillin secretion by arthropods 25 and the demonstration of active beta-lactamase in vertebrates including humans 19 , as well as in archaea 6 and fungi 26 show that MBL fold proteins have a dramatically broad distribution. In humans, 18 genes were annotated as beta-lactamases, whose activity had not been biologically-tested until recently 19 .…”

“…Thus, the recent description of penicillin secretion by arthropods 25 and the demonstration of active beta-lactamase in vertebrates including humans 19 , as well as in archaea 6 and fungi 26 show that MBL fold proteins have a dramatically broad distribution. In humans, 18 genes were annotated as beta-lactamases, whose activity had not been biologically-tested until recently 19 . In addition, MBL fold proteins were highlighted to digest DNA or RNA 2,19 .…”

“…In humans, 18 genes were annotated as beta-lactamases, whose activity had not been biologically-tested until recently 19 . In addition, MBL fold proteins were highlighted to digest DNA or RNA 2,19 . Thus, a class of enzymes, that were named beta-lactamases because of their original discovery in bacteria resistant to beta-lactamines, are in fact potentially versatile proteins.…”

“…Phylogeny reconstruction was performed after amino acid sequence alignment with the Muscle program 33 and the Maximum-Likelihood method using FastTree 34 , and tree visualization used MEGA 6 software 35 . The amino acid sequences analyzed are Tupanvirus deep ocean protein AUL78925.1 and its homologs with the greatest BLASTp scores from the NCBI GenBank protein sequence database, our sequence database of giant virus genomes, and previously described draft genome sequences from 14 Acanthamoeba species 36 ; a set of previously described MBL fold proteins 19 ; and a set of sequences from the UniProtKB database 1 previously used for phylogeny reconstructions. Three-dimensional comparisons for protein modeling, prediction and analysis were carried out against the Phyre2 web portal 18 .…”