Bordetella pertussis tracheal cytotoxin and other muramyl peptides: Distinct structure-activity relationships for respiratory epithelial cytopathology

Kathryn E. Luker, Jayne L. Collier, Eric W. Kolodziej, Garland R. Marshall, William E. Goldman

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Tracheal cytotoxin (TCT) is a disaccharidetetrapeptide released by Bordetella pertussis, the causative agent of pertussis (whooping cough). We have previously determined the structure of TCT to be GlcNAc-1,6-anhydroMurNAc-L-Ala-γ-D-Glu-meso-A2pm-D-Ala, where MurNAc = N-acetylmuramic acid and A2pm = diaminopimelic acid. Purified TCT reproduces the respiratory cytopathology observed during pertussis, including ciliostasis and extrusion of ciliated cells. We have tested structural analogs of TCT for their ability to reproduce native TCT toxicity in explanted hamster tracheal tissue and hamster trachea epithelial (HTE) cell cultures. Other investigators have evaluated many of these analogs, which are muramyl or desmuramyl peptides, for muramyl peptide activities such as immunopotentiation, induction of slow-wave sleep, and pyrogenicity. Four desmuramyl peptides were produced in our laboratory from B. pertussis peptidoglycan or by chemical synthesis, including unusual peptides containing α-aminopimelic acid in place of A2pm. Based on the relative ability of compounds to inhibit DNA synthesis in HTE cells, truncated analogs lacking A2pm entirely or lacking only the side-chain amine or carboxyl group of A2pm were less active than TCT by a factor of at least 1000. All active analogs included a native or near-native peptide moiety, independent of the presence, absence, or substitution of the sugar moiety. We conclude that the structural requirements for TCT toxicity differ considerably from those for most other muramyl peptide activities, in that the disaccharide moiety is irrelevant for toxicity and both the free amino and carboxyl groups of the A2pm side chain are required for activity.

Original languageEnglish
Pages (from-to)2365-2369
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number6
DOIs
StatePublished - Mar 15 1993

Keywords

  • Bacterial toxins
  • Diaminopimelic acid
  • Muramyl dipeptide
  • Peptidoglycan
  • Pertussis

Fingerprint

Dive into the research topics of 'Bordetella pertussis tracheal cytotoxin and other muramyl peptides: Distinct structure-activity relationships for respiratory epithelial cytopathology'. Together they form a unique fingerprint.

Cite this