Multiple Low-Reactivity Class B Penicillin-Binding Proteins Are Required for Cephalosporin Resistance in Enterococci. Antimicrob Agents Chemother 2020 Mar 24;64(4)
Date
02/12/2020Pubmed ID
32041714Pubmed Central ID
PMC7179317DOI
10.1128/AAC.02273-19Scopus ID
2-s2.0-85082388512 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
Enterococcus faecalis and Enterococcus faecium are commensals of the gastrointestinal tract of most terrestrial organisms, including humans, and are major causes of health care-associated infections. Such infections are difficult or impossible to treat, as the enterococcal strains responsible are often resistant to multiple antibiotics. One intrinsic resistance trait that is conserved among E. faecalis and E. faecium is cephalosporin resistance, and prior exposure to cephalosporins is one of the most well-known risk factors for acquisition of an enterococcal infection. Cephalosporins inhibit peptidoglycan biosynthesis by acylating the active-site serine of penicillin-binding proteins (PBPs) to prevent the PBPs from catalyzing cross-linking during peptidoglycan synthesis. For decades, a specific PBP (known as Pbp4 or Pbp5) that exhibits low reactivity toward cephalosporins has been thought to be the primary PBP required for cephalosporin resistance. We analyzed other PBPs and report that in both E. faecalis and E. faecium, a second PBP, PbpA(2b), is also required for resistance; notably, the cephalosporin ceftriaxone exhibits a lethal effect on the ΔpbpA mutant. Strikingly, PbpA(2b) exhibits low intrinsic reactivity with cephalosporins in vivo and in vitro Unlike the Δpbp5 mutant, the ΔpbpA mutant exhibits a variety of phenotypic defects in growth kinetics, cell wall integrity, and cellular morphology, indicating that PbpA(2b) and Pbp5(4) are not functionally redundant and that PbpA(2b) plays a more central role in peptidoglycan synthesis. Collectively, our results shift the current understanding of enterococcal cephalosporin resistance and suggest a model in which PbpA(2b) and Pbp5(4) cooperate to coordinately mediate peptidoglycan cross-linking in the presence of cephalosporins.
Author List
Djorić D, Little JL, Kristich CJAuthors
Dusanka Djoric Research Scientist I in the Microbiology and Immunology department at Medical College of WisconsinChristopher J. Kristich PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AcylationCephalosporin Resistance
Cross Infection
Electrophoresis, Polyacrylamide Gel
Enterococcus faecalis
Enterococcus faecium
Gastrointestinal Tract
Humans
Immunoblotting
Inhibitory Concentration 50
Microscopy, Electron, Transmission
Penicillin-Binding Proteins
Peptidoglycan
