Rs. Roy et al., In vivo processing and antibiotic activity of microcin B17 analogs with varying ring content and altered bisheterocyclic sites, CHEM BIOL, 6(5), 1999, pp. 305-318
Background: The Escherichia coli peptide antibiotic microcin B17 (MccB17) c
ontains four oxazole and four thiazole rings, and inhibits DNA gyrase,The r
ole of individual and tandem pairs of heterocycles in bioactivity has not b
een determined previously.
Results: The two tandem 4,2-bisheterocycles in MccB17 were varied by expres
sion of MccB17 or mutants containing altered sequences at Gly39-Ser40-Cys41
or Gly54-Cys55-Ser56. A mixture of five-nine-ring MccB17 isoforms were sep
arated and quantitated for antibiotic potency. Mutagenesis of the thiazole-
oxazole pair significantly affected antibiotic activity compared with the u
pstream oxazole-thiazole, which might stabilize partially cyclized intermed
iates against proteolysis.
Conclusions: Enzymatic heterocyclization in native MccB17 occurs distributi
vely, Antibiotic activity correlates with the number of rings and is differ
entially sensitive to both the location and the identity of the 4,2-tandem
heterocycle pairs in MccB17. Such tandem heterocycles might be useful pharm
acophores in combinatorial libraries.