Effects of elfamycins on elongation factor Tu from Escherichia coli and Staphylococcus aureus.
Six kirromycin analogs (elfamycins) were compared on the basis of their inhibition of Escherichia coli poly(U)-directed poly(Phe) synthesis and stimulation of elongation factor Tu (EF-Tu)-associated GTPase activity. The elfamycins tested were kirromycin, aurodox, efrotomycin, phenelfamycin A, unphenelfamycin, and L-681,217. The last three lack the pyridone ring present in the other elfamycins. All the elfamycins inhibited poly(U)-dependent poly(Phe) synthesis and stimulated EF-Tu-associated GTPase activity, suggesting that the pyridone ring is not essential for activity. The six elfamycins were also examined in a poly(U)-directed, poly(Phe)-synthesizing system derived from Staphylococcus aureus and had 50% inhibitory concentrations of greater than or equal to 1 mM. When S. aureus ribosomes and E. coli elongation factors were combined in a hybrid poly(Phe)-synthesizing system, aurodox produced essentially complete inhibition of poly(Phe) synthesis with a 50% inhibitory concentration of 0.13 microM. This suggests that the observed high MICs of kirromycin and its congeners in S. aureus reflect a kirromycin-resistant EF-Tu rather than permeability constraints.
Hall
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Roche Research Center, Nutley, New Jersey 07110.
Watkins
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JD
Georgopapadakou
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NH
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000899:Aurodox / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism*; D020963:GTP Phosphohydrolase-Linked Elongation Factors / Q000378:metabolism; D006824:Hybridization, Genetic; D010444:Peptide Elongation Factor Tu / Q000378:metabolism*; D010649:Phenylalanine / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D011728:Pyridones / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D010761:Phosphorus Radioisotopes; D011728:Pyridones; D000899:Aurodox; D010649:Phenylalanine; D020963:GTP Phosphohydrolase-Linked Elongation Factors; D010444:Peptide Elongation Factor Tu; C008536:mocimycin