title: Cell Wall Recycling-Linked Coregulation of AmpC and PenB β-Lactamases through ampD Mutations in Burkholderia cenocepacia.
abstract: In many Gram-negative pathogens, mutations in the key cell wall-recycling enzyme AmpD (N-acetyl-anhydromuramyl-L-alanine amidase) affect the activity of the regulator AmpR, which leads to the expression of AmpC β-lactamase, conferring resistance to expanded-spectrum cephalosporin antibiotics. Burkholderia cepacia complex (Bcc) species also have these Amp homologs; however, the regulatory circuitry and the nature of causal ampD mutations remain to be explored. A total of 92 ampD mutants were obtained, representing four types of mutations: single nucleotide substitution (causing an amino acid substitution or antitermination of the enzyme), duplication, deletion, and IS element insertion. Duplication, which can go through reversion, was the most frequent type. Intriguingly, mutations in ampD led to the induction of two β-lactamases, AmpC and PenB. Coregulation of AmpC and PenB in B. cenocepacia, and likely also in many Bcc species with the same gene organization, poses a serious threat to human health. This resistance mechanism is of evolutionary optimization in that ampD is highly prone to mutations allowing rapid response to antibiotic challenge, and many of the mutations are reversible in order to resume cell wall recycling when the antibiotic challenge is relieved.
authors.affiliation: Department of Biomedical Sciences, Korea University, Anam-Dong, Seongbuk-Gu, Seoul, South Korea.
authors.forename: Junghyun
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Biomedical Sciences, Korea University, Anam-Dong, Seongbuk-Gu, Seoul, South Korea hstanleykim@korea.ac.kr.
authors.forename: Heenam Stanley
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D057508:Burkholderia cenocepacia / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018550:Cephalosporin Resistance / Q000235:genetics*; D002511:Cephalosporins / Q000494:pharmacology; D004251:DNA Transposable Elements; D015964:Gene Expression Regulation, Bacterial; D005816:Genetic Complementation Test; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D009238:N-Acetylmuramoyl-L-alanine Amidase / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; D004251:DNA Transposable Elements; D007527:Isoenzymes; C062460:AmpD protein, Bacteria; D009238:N-Acetylmuramoyl-L-alanine Amidase; C048795:AmpC beta-lactamases; D001618:beta-Lactamases