tiamulin and Staphylococcal-Infections

A series of novel pleuromutilin derivatives with substituted 6-methylpyrimidine moieties was designed, synthesized, and evaluated for their antibacterial activities. Most of the tested compounds exhibited potent antibacterial activities against Staphylococcus aureus ATCC 25923 (S. aureus-25923), methicillin-resistant Staphylococcus epidermidis ATCC 51625 (MRSE-51625), methicillin-resistant Staphylococcus aureus BNCC 337371 (MRSA-337371), Streptococcus dysgalactiae (S. dysgalactiae) and Streptococcus agalactiae (S. agalactiae). Compounds 5c and 5g were the most active and displayed bacteriostatic activities against MRSA. In vivo mouse systemic infection experiment showed that 5c significantly improved the survival rate of mice (ED

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Drug Design; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Models, Molecular; Pleuromutilins; Polycyclic Compounds; Pyrimidines; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Staphylococcus epidermidis; Streptococcus; Streptococcus agalactiae

Topics: Aniline Compounds; Animals; Anti-Bacterial Agents; Diterpenes; Drug Design; Escherichia coli; Escherichia coli Infections; Female; Humans; Methicillin-Resistant Staphylococcus aureus; Mice, Inbred ICR; Pleuromutilins; Polycyclic Compounds; Staphylococcal Infections; Staphylococcus aureus

We synthesized a series of novel thioether pleuromutilin derivatives incorporating 2-aminothiophenol moieties into the C14 side chain via acylation reactions under mild conditions. We evaluated the in-vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300), Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC 25922). The majority of the synthesized derivatives possessed moderate antibacterial activities. Compound 8 was found to be the most active antibacterial derivative against MRSA. We conducted docking experiments to understand the possible mode of interactions between compounds 8, 9b, 11a and 50S ribosomal subunit. The docking results proved that there is a reasonable correlation between the binding free energy and the antibacterial activity. Compound 8 was evaluated for its in-vivo antibacterial activity and showed higher efficacy than tiamulin against MRSA in mouse infection model.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Binding Sites; Deinococcus; Diterpenes; Escherichia coli; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Peptidyl Transferases; Phenols; Pleuromutilins; Polycyclic Compounds; Protein Structure, Tertiary; Ribosome Subunits, Large, Bacterial; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Sulfhydryl Compounds

The cfr gene was identified in three linezolid-resistant USA300 methicillin-resistant Staphylococcus aureus (MRSA) isolates collected over a 3-day period at a New York City medical center in 2011 as part of a routine surveillance program. Each isolate possessed a plasmid containing a pSCFS3-like cfr gene environment. Transformation of the cfr-bearing plasmids into the S. aureus ATCC 29213 background recapitulated the expected Cfr antibiogram, including resistance to linezolid, tiamulin, clindamycin, and florfenicol and susceptibility to tedizolid.

Topics: Acetamides; Anti-Bacterial Agents; Bacterial Proteins; Clindamycin; Diterpenes; Drug Resistance, Multiple, Bacterial; Gene Transfer Techniques; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Sequence Data; New York; Organophosphates; Oxazoles; Oxazolidinones; Plasmids; Staphylococcal Infections; Thiamphenicol

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Drug Resistance, Multiple, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Swine

Methicillin-resistant Staphylococcus aureus clonal lineage ST398 and methicillin-susceptible lineage ST9 strains have their main reservoir in swine but can colonize and cause infections in humans. The phenicol/lincosamide/oxazolidinone/pleuromutilin/streptogramin A multidrug resistance gene cfr was detected in isolates of both clonal lineages, rendering a spread to humans with exposure to swine farming possible.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Plasmids; Staphylococcal Infections; Staphylococcus aureus; Swine

A novel ABC transporter gene, vga(C), was identified on the 14,365-bp multiresistance plasmid pKKS825 in a porcine methicillin (meticillin)-resistant Staphylococcus aureus isolate of sequence type 398. The vga(C) gene encodes a 523-amino-acid protein which confers resistance not only to streptogramin A antibiotics but also to lincosamides and pleuromutilins. Plasmid pKKS825 also carries the resistance genes aadD, tet(L), and dfrK, which may enable the coselection of vga(C) under selective pressure by kanamycin/neomycin, tetracyclines, and trimethoprim.

Topics: Animals; Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Diterpenes; Drug Resistance, Multiple, Bacterial; Kanamycin; Lincosamides; Methicillin-Resistant Staphylococcus aureus; Molecular Sequence Data; Neomycin; Plasmids; Pleuromutilins; Polycyclic Compounds; Staphylococcal Infections; Streptogramin A; Swine; Swine Diseases; Tetracyclines; Trimethoprim

Following recent reports of ribosomal protein L3 mutations in laboratory-derived linezolid-resistant (LZD(r)) Staphylococcus aureus, we investigated whether similar mutations were present in LZD(r) staphylococci of clinical origin. Sequence analysis of a variety of LZD(r) isolates revealed two L3 mutations, DeltaSer145 (S. aureus NRS127) and Ala157Arg (Staphylococcus epidermidis 1653059), both occurring proximal to the oxazolidinone binding site in the peptidyl transferase center. The oxazolidinone torezolid maintained a >or=8-fold potency advantage over linezolid for both strains.

Topics: Acetamides; Binding Sites; Drug Resistance, Bacterial; Linezolid; Mutation; Oxazolidinones; Protein Structure, Secondary; Ribosomal Protein L3; Ribosomal Proteins; RNA, Ribosomal, 23S; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Tetrazoles

Susceptibilities to metabolites of tiamulin (TIA) and enrofloxacin (ENR) were tested using selected bacteria with previously defined minimal inhibitory concentrations (MIC). The TIA metabolites tested were: N-deethyl-tiamulin (DTIA), 2beta-hydroxy-tiamulin (2beta-HTIA) and 8alpha-hydroxy-tiamulin (8alpha-HTIA), and the ENR metabolites were: ciprofloxacin (CIP) and enrofloxacin N-oxide (ENR-N). Bacteria, all of porcine origin, were selected as representatives of bacterial infections (Staphylococcus hyicus and Actinobacillus pleuropneumoniae), zoonotic bacteria (Campylobacter coli) and indicator bacteria (Escherichia coli and enterococci). Furthermore the effects of these compounds were tested on the microbial community of active sludge to test any negative effect on colony forming units (CFU). DTIA had a potency of 12.5-50% of the potency of TIA. 2beta-HTIA and 8alpha-HTIA had potencies less than 1% of the potency of TIA. ENR-N had a potency of 0.75-1.5% of the potency of ENR, while CIP and ENR had similar potencies. Results obtained here indicate that CIP and DTIA could contribute to the selective pressure for upholding antimicrobial resistant bacteria in animals under ENR or TIA treatment. The most potent metabolites CIP and DTIA showed considerable potencies against activated sludge bacteria compared to the parent compounds. EC(50) (microg/ml) for ENR, CIP, TIA and DTIA were 0.018 [95% CI: 0.028-0.149], 0.064 [95% CI: 0.007-0.046], 6.0 [95% CI: 3.6-9.8], and 9.7 [95% CI: 5.8-16.3], respectively. This indicates that the compounds can change the bacterial population in the sludge, and hereby alter the properties of the sludge.

Topics: Actinobacillus Infections; Actinobacillus pleuropneumoniae; Animals; Anti-Bacterial Agents; Diterpenes; Drug Resistance, Bacterial; Enrofloxacin; Fluoroquinolones; Microbial Sensitivity Tests; Sewage; Staphylococcal Infections; Staphylococcus aureus; Swine; Swine Diseases