tiamulin and retapamulin

Due to the rapid onset of resistance to most antibacterial drugs, research efforts are focusing on new classes of antibacterials with different mechanisms of action from clinically used antibacterials. Pleuromutilin derivatives have received more and more scientific attention for their unique mechanism of action. Two pleuromutilin derivatives, tiamulin and valnemulin have been successfully developed as antibiotics for veterinary use. Retapamulin, another pleuromutilin derivative has been approved for use in humans in April 2007 by Food and Drug Administration (FDA). It has been shown that there is rarely cross-resistance between pleuromutilin derivatives and other antimicrobial agents, and the development of resistance bacterial is still low. This review will demonstrate mechanism of action of pleuromutilin derivatives and reveal the structure-activity relationship (SAR) of pleuromutilin derivatives. Additionally, the pleuromutilin antibacterial derivative agents in the market, such as tiamulin, valnemulin and retapamulin, will be discussed. It is proposed that new antibacterial agents might be developed from pleuromutilin derivatives in the future.

Topics: Animals; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Microbial; Humans; Pleuromutilins; Polycyclic Compounds; Structure-Activity Relationship

Mutilins derivatives, which were successfully developed in veterinary medicines such as tiamulin and valnemulin, have regained interest as promising antibacterial agents with potential for human use in the past few years. In 2007, Retapamulin, as the first in a new class of topical antibacterial in the nearly two decades, was approved for use in human skin infections. This review provides a developed process of mutilins derivatives from veterinary to human-used antibiotics and emphasizes the structure activity relationship (SAR) and antibacterial mechanism of mutilins derivatives. Moreover, the semi-synthetic strategy of water-soluble mutilins derivatives and related novel derivatives during 2006-2008 will also be reviewed.

Topics: Animals; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Humans; Ketones; Pleuromutilins; Polycyclic Compounds; Structure-Activity Relationship

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bridged Bicyclo Compounds, Heterocyclic; Clarithromycin; Diterpenes; Humans; Josamycin; Linezolid; Macrolides; Oomycetes; Oxazolidinones; Phosphorylcholine; Pleuromutilins; Polycyclic Compounds; Pythiosis; Pythium

Retapamulin MICs of > or =2 microg/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Pleuromutilins; Polycyclic Compounds; Sequence Analysis, DNA; Staphylococcus aureus

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.

Topics: Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Pleuromutilins; Polycyclic Compounds; Ribosomal Protein L3; Ribosomal Proteins; Staphylococcus aureus