Journal of Antimicrobial Chemotherapy, Vol 41, 179-187, Copyright © 1998 by The British Society for Antimicrobial Chemotherapy
F Doucet-Populaire, JO Capobianco, D Zakula, V Jarlier and RC Goldman
Clarithromycin, the 6-O-methyl derivative of erythromycin, is approved for
treatment of Mycobacterium avium infections and for prophylaxis in patients
at risk. Since clarithromycin is more active against mycobacteria than the
parent compound, erythromycin, we evaluated the interaction of erythromycin
and clarithromycin with cells and ribosomes isolated from M. avium and
Mycobacterium smegmatis. The MIC of clarithromycin was 32 and 64 times
lower than that of erythromycin for M. smegmatis and M. avium,
respectively. The cellular uptake rate for clarithromycin was two- to
five-fold faster than for erythromycin, and cell-associated clarithromycin
reached a plateau two-fold higher than that of erythromycin after 3 h.
Energy was not required for uptake. Fractionation of cell-associated
clarithromycin yielded 12% in the walls, 21% bound to ribosomes, with the
remainder being lost during work-up. In addition, three- to six-fold more
clarithromycin was associated with the isolated cell integument compared
with erythromycin. The Kd for clarithromycin binding to ribosomes was 2.9-
and 3.5-fold tighter for M. smegmatis and M. avium, respectively, than for
erythromycin, due mainly to a slower off-rate. The log partition
coefficients of the non-ionized form (log Pu) for clarithromycin and
erythromycin were 3.24 and 2.92, respectively. Thus clarithromycin is more
hydrophobic than erythromycin. This would favour more rapid diffusion
within and across hydrophobic regions of the cell integument, since once a
solute saturates a membrane the net flux across the membrane must equal the
net flux within the membrane as dictated by diffusion. We conclude that the
lower MIC of clarithromycin for M. avium and M. smegmatis is due to a
combination of increased cellular uptake, the major factor, possibly
through a peripheral hydrophobic layer, and increased binding affinity to
ribosomes.
ORIGINAL ARTICLES
Molecular basis of clarithromycin activity against Mycobacterium avium and Mycobacterium smegmatis
Laboratoire de Recherche sur les Mecanismes d'Action des Antibiotiques, Universite Paris VI, Faculte de Medecine Pitie-Salpetriere, France.
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