Biophysical study of the mode of action of the tetracycline antibiotics. Inhibition of metalloflavoenzyme NADH cytochrome oxidoreductase

John L. Colaizzi, Adelbert M. Knevel, Alfred N. Martin

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

A considerable amount of evidence indicates that the tetracyclines may produce their antibiotic action by inhibition of metalloflavoenzymes. In this investigation the inhibitory properties of a series of biologically active and inactive tetracycline analogs on the metalloflavoenzyme, NADH–cytochrome c oxidoreductase, were investigated. Those analogs capable of inhibiting the enzyme appeared to act, at least partially, by chelation of enzyme‐bound metal. The site of chelation on the tetracycline molecule appeared to be the C‐11 to C‐12 chromophore, or the C‐1, C‐2, C‐3 region involving the 2‐carboxamide group of the tetracycline molecule. Both modification of the 2‐carboxamide substituent and epimerization of the 4‐dimethyl‐amino group resulted in loss of inhibitory effect. This parallels known structure‐antibiotic activity relationships for these compounds. Inactive isotetracycline, tetracycline methiodide, and dedimethylaminotetracycline were able to inhibit the enzyme at least as well as the parent tetracyclines. These compounds might lack antibiotic activity due to inability to enter bacterial cells.

Original languageEnglish (US)
Pages (from-to)1425-1436
Number of pages12
JournalJournal of Pharmaceutical Sciences
Volume54
Issue number10
DOIs
StatePublished - Oct 1965
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

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