Affiliation:
1. Department of Microbiology, MMPD-CEDD, GlaxoSmithKline, Collegeville, Pennsylvania 19426
Abstract
ABSTRACT
To assess their effects on susceptibility to retapamulin in
Staphylococcus aureus
, first-, second-, and third-step mutants with elevated MICs to tiamulin and other investigational pleuromutilin compounds were isolated and characterized through exposure to high drug concentrations. All first- and second-step mutations were in
rplC
, encoding ribosomal protein L3. Most third-step mutants acquired a third mutation in
rplC
. While first- and second-step mutations did cause an elevation in tiamulin and retapamulin MICs, a significant decrease in activity was not seen until a third mutation was acquired. All third-step mutants exhibited severe growth defects, and faster-growing variants arose at a high frequency from most isolates. These faster-growing variants were found to be more susceptible to pleuromutilins. In the case of a mutant with three alterations in
rplC
, the fast-growing variants acquired an additional mutation in
rplC
. In the case of fast-growing variants of isolates with two mutations in
rplC
and at least one mutation at an unmapped locus, one of the two
rplC
mutations reverted to wild type. These data indicate that mutations in
rplC
that lead to pleuromutilin resistance have a direct, negative effect on fitness. While reduction in activity of retapamulin against
S. aureus
can be seen through mutations in
rplC
, it is likely that target-specific resistance to retapamulin will be slow to emerge due to the need for three mutations for a significant effect on activity and the fitness cost of each mutational step.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
74 articles.
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