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ANTIMICROB. AGENTS CHEMOTHER.
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action between the phospholipid acyl chains and some proteins
that are membrane bound (1). The hydroxyl groups of the
galloyl moiety would be placed near the lipid-water interface,
where they could form hydrogen bonds with water and may
also promote other types of interaction with the polar part of
the phospholipid. These polar interactions will keep the alkyl
gallate molecules in the upper part of the membrane. Such a
location would perturb the membrane interiors, and the result-
ing restrictions on the fluidity of membrane components could
sterically hinder substrate diffusion for PBPs, especially for
PBP2a, and thereby decrease the kinetics of cell wall biosyn-
thesis. Consequently, the alkyl gallates would cause a dramatic
decrease in the MICs of -lactams for MRSA strains. This is
compatible with our hypothesis on the action mechanism of
ILSMRs presented previously (29, 30).
Animal experiments performed with propyl, octyl, and do-
decy gallates showed that no effects were observed at a dose
level of 1,000 mg/kg of feed, a level that was adopted as the
no-effect level by the FAO-WHO Joint Expert Committee on
Food Additives in 1976 (38). In Japan, propyl and octyl gallates
are recognized as quasi drugs by the Minister of Health, La-
bour and Welfare of Japan. These results indicate that gallates
may be used safely not only as additives but also in clinical
applications.
The results presented in this report highlight the potential of
alkyl gallates to produce ILSMR leads with strong activity
against a multidrug-resistant strain. Further work is presently
under way to characterize the action mechanisms of these
interesting compounds against multidrug-resistant S. aureus.
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