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Antimicrob Agents Chemother. 2007 Aug;51(8):2937-42. Epub 2007 May 14.

Cytoplasmic-membrane anchoring of a class A beta-lactamase and its capacity in manifesting antibiotic resistance.

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  • 1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.


Bacterial beta-lactamases are the major causes of resistance to beta-lactam antibiotics. Three classes of these enzymes are believed to have evolved from ancestral penicillin-binding proteins (PBPs), enzymes responsible for bacterial cell wall biosynthesis. Both beta-lactamases and PBPs are able to efficiently form acyl-enzyme species with beta-lactam antibiotics. In contrast to beta-lactamases, PBPs are unable to efficiently turn over antibiotics and therefore are susceptible to inhibition by beta-lactam compounds. Although both PBPs and gram-negative beta-lactamases operate in the periplasm, PBPs are anchored to the cytoplasmic membrane, but beta-lactamases are not. It is believed that beta-lactamases shed the membrane anchor in the course of evolution. The significance of this event remains unclear. In an attempt to demonstrate any potential influence of the membrane anchor on the overall biological consequences of beta-lactamases, we fused the TEM-1 beta-lactamase to the C-terminal membrane-anchor of penicillin-binding protein 5 (PBP5) of Escherichia coli. The enzyme was shown to express well in E. coli and was anchored to the cytoplasmic membrane. Expression of the anchored enzyme did not result in any changes in antibiotic resistance pattern of bacteria or growth rates. However, in the process of longer coincubation, the organism that harbored the plasmid for the anchored TEM-1 beta-lactamase lost out to the organism transformed by the plasmid for the nonanchored enzyme over a period of 8 days of continuous growth. The effect would appear to be selection of a variant that eliminates the problematic protein through elimination of the plasmid that encodes it and not structural or catalytic effects at the protein level. It is conceivable that an evolutionary outcome could be the shedding of the sequence for the membrane anchor or alternatively evolution of these enzymes from nonanchored progenitors.

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