Generation of thiocillin variants by prepeptide gene replacement and in vivo processing by Bacillus cereus.
The thiocillins are natural-product antibiotics derived from ribosomally encoded peptides that undergo extensive posttranslational modifications to yield the mature trithiazolylpyridine-containing macrocyclic compound. Poor pharmacokinetic properties have prevented the clinical use of these highly potent antibiotics. Through in vivo manipulation of the gene responsible for production of the thiocillin precursor peptide, we have generated 65 novel thiocillin variants, allowing us to explore structure-activity relationships involved in both precursor peptide maturation and antibiotic activity.
Acker
Michael G
MG
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bowers
Albert A
AA
Walsh
Christopher T
CT
D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D001409:Bacillus cereus / Q000235:genetics* / Q000378:metabolism*; D055786:Gene Knockout Techniques; D005798:Genes, Bacterial / Q000235:genetics*; D005818:Genetic Engineering; D009154:Mutation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D010455:Peptides; C012574:thiocillin