The antibiotic microcin B17 is a DNA gyrase poison: characterisation of the mode of inhibition.
Microcin B17 is a 3.1-kDa bactericidal peptide; the putative target of this antibiotic is DNA gyrase. Microcin B17 has no detectable effect on gyrase-catalysed DNA supercoiling or relaxation activities in vitro and is unable to stabilise DNA cleavage in the absence of nucleotides. However, in the presence of ATP, or the non-hydrolysable analogue 5'-adenylyl beta,gamma-imidodiphosphate, microcin B17 stabilises a gyrase-dependent DNA cleavage complex in a manner reminiscent of quinolones, Ca(2+), or the bacterial toxin CcdB. The pattern of DNA cleavage produced by gyrase in the presence of microcin B17 is different from that produced by quinolones and more closely resembles Ca(2+)-mediated cleavage. Several gyrase mutants, including well-known quinolone-resistant mutants, are cross resistant to microcin-induced DNA cleavage. We suggest that microcin exerts its effects through a mechanism that has similarities to those of both the bacterial toxin CcdB and the quinolone antibacterial agents.
Heddle
J G
JG
Department of Biochemistry, University of Leicester, Leicester, LE1 7RH, UK.
Blance
S J
SJ
Zamble
D B
DB
Hollfelder
F
F
Miller
D A
DA
Wentzell
L M
LM
Walsh
C T
CT
Maxwell
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000266:Adenylyl Imidodiphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology; D001430:Bacteriocins / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002939:Ciprofloxacin / Q000737:chemistry / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D027081:DNA Gyrase; D004261:DNA Replication / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D019384:Nucleic Acid Synthesis Inhibitors; D010455:Peptides; D011487:Protein Conformation; D015363:Quinolones / Q000494:pharmacology; D013379:Substrate Specificity; D059005:Topoisomerase II Inhibitors; D015003:Yeasts / Q000201:enzymology
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001430:Bacteriocins; C068356:CcdB protein, Plasmid F; D003374:Coumarins; D003603:Cytotoxins; D004278:DNA, Superhelical; D019384:Nucleic Acid Synthesis Inhibitors; D010455:Peptides; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; C020411:microcin; D000266:Adenylyl Imidodiphosphate; D002939:Ciprofloxacin; D000255:Adenosine Triphosphate; D004259:DNA-Directed DNA Polymerase; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II; D002118:Calcium