Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin

被引:66
作者
Gentry, Daniel R. [1 ]
Rittenhouse, Stephen F. [1 ]
McCloskey, Lynn [1 ]
Holmes, David J. [1 ]
机构
[1] GlaxoSmithKline, Dept Microbiol, MMPD CEDD, Collegeville, PA 19426 USA
关键词
D O I
10.1128/AAC.01066-06
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:2048 / 2052
页数:5
相关论文
共 9 条
[1]   GENETIC-ANALYSIS OF EPIDERMIN BIOSYNTHETIC GENES AND EPIDERMIN-NEGATIVE MUTANTS OF STAPHYLOCOCCUS-EPIDERMIDIS [J].
AUGUSTIN, J ;
ROSENSTEIN, R ;
WIELAND, B ;
SCHNEIDER, U ;
SCHNELL, N ;
ENGELKE, G ;
ENTIAN, KD ;
GOTZ, F .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1992, 204 (03) :1149-1154
[2]  
BOCK A, 1982, J BACTERIOL, V151, P1253
[3]   Resistance to the peptidyl transferase inhibitor tiamulin caused by mutation of ribosomal protein L3 [J].
Bosling, J ;
Poulsen, SM ;
Vester, B ;
Long, KS .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2003, 47 (09) :2892-2896
[4]   Pleuromutilin antibiotics [J].
Hunt, E .
DRUGS OF THE FUTURE, 2000, 25 (11) :1163-1168
[5]   Single- and multistep resistance selection studies on the activity of retapamulin compared to other agents against Staphylococcus aureus and Streptococcus pyogenes [J].
Kosowska-Shick, K ;
Clark, C ;
Credito, K ;
McGhee, P ;
Dewasse, B ;
Bogdanovich, T ;
Appelbaum, PC .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2006, 50 (02) :765-769
[6]  
NCCLS, 2003, M7A6 NCCLS
[7]   The pleuromutilin drugs tiamulin and valnemulin bind to the RNA at the peptidyl transferase centre on the ribosome [J].
Poulsen, SM ;
Karlsson, M ;
Johansson, LB ;
Vester, B .
MOLECULAR MICROBIOLOGY, 2001, 41 (05) :1091-1099
[8]   Mutations in ribosomal protein L3 and 23S ribosomal RNA at the peptidyl transferase centre are associated with reduced susceptibility to tiamulin in Brachyspira spp. isolates [J].
Pringle, M ;
Poehlsgaard, J ;
Vester, B ;
Long, KS .
MOLECULAR MICROBIOLOGY, 2004, 54 (05) :1295-1306
[9]   Inhibition of peptide bond formation by pleuromutilins:: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin [J].
Schlünzen, F ;
Pyetan, E ;
Fucini, P ;
Yonath, A ;
Harms, JM .
MOLECULAR MICROBIOLOGY, 2004, 54 (05) :1287-1294