Ev. Stabb et J. Handelsman, GENETIC-ANALYSIS OF ZWITTERMICIN-A RESISTANCE IN ESCHERICHIA-COLI - EFFECTS ON MEMBRANE-POTENTIAL AND RNA-POLYMERASE, Molecular microbiology, 27(2), 1998, pp. 311-322
Zwittermicin A is a novel aminopolyol antibiotic that represents a new
structural class of antibiotic and has diverse biological activities,
including the suppression of plant disease and the ability to inhibit
prokaryotic and eukaryotic cells. To enhance our fundamental understa
nding and applications of zwittermicin A, we elucidated mechanisms of
zwittermicin A resistance in Escherichia coli. Two classes of zwitterm
icin A-resistant mutants of E. coli were selected and characterized. O
ne class included mutants altered in hemA, hemB, hemL, ubi, cydAB or a
tp, which were defective in generating a proton motive force (PMF) and
resistant to aminoglycosides. The mutant analysis, coupled with physi
ological data, indicated an association between the electrical membran
e potential (Delta Psi) component of PMF and zwittermicin A sensitivit
y. A second class of zwittermicin A-resistant mutants was aminoglycosi
de sensitive and was affected in rpoB and rpoC, genes that encode subu
nits of RNA polymerase. The rpoB and rpoC mutants suggested that zwitt
ermicin A might inhibit transcription, DNA replication, DNA gyrase or
topoisomerase I; however, we found no further evidence to support any
of these as the target for zwittermicin A. This study elucidated the g
enetic mechanisms of zwittermicin A resistance in E. coli. The results
suggest that Delta Psi drives zwittermicin A uptake, and that, unlike
other antibiotics for which resistance maps in rpoB or rpoC, zwitterm
icin A does not cause the rapid cessation of DNA or RNA synthesis, sug
gesting a unique mechanism of antibiosis.