RESUMO
The oxazolidinones are a new class of synthetic antibacterials effective against a broad range of pathogenic Gram-positive bacteria, including multi-drug-resistant strains. Linezolid is the first drug from this class to reach the market and has become an important new option for the treatment of serious infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus faecium (VRE). In the search for novel oxazolidinones with improved potency and spectrum, we have prepared and evaluated the antibacterial properties of conformationally constrained analogues in which the morpholine ring of linezolid is replaced with various substituted azabicyclo[3.1.0]hexyl ring systems. Several classes of azabicyclic analogues were identified with activity comparable or superior to that of linezolid. These include analogues bearing hydroxyl, amino, amido, or carboxyl groups on the azabicyclic ring. The azabicyclic acid analogue 50 was 4 times more potent than linezolid against key Gram-positive and fastidious Gram-negative pathogens (S. aureus, Streptococcus pneumoniae, and E. faecalis MICs < or = 1 microg/mL; Haemophilus influenzae MIC = 4 microg/mL).
Assuntos
Antibacterianos/síntese química , Compostos Aza/síntese química , Oxazolidinonas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Farmacorresistência Bacteriana , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: Dalbavancin is a novel, semi-synthetic glycopeptide antibiotic. The aim of this study was to further explore its activity against staphylococci. METHODS: The bactericidal activity of dalbavancin was studied using MBC and time-kill methods. The potential for resistance to dalbavancin was examined using single-step and serial-passage experiments. RESULTS: Dalbavancin was bactericidal against methicillin-susceptible and -resistant Staphylococcus aureus, in both the presence and absence of human serum. No resistance was seen with any isolate tested. After serial passage, bacterial populations were more homogeneous in their susceptibility to dalbavancin than to vancomycin or teicoplanin. CONCLUSION: Dalbavancin is bactericidal for staphylococci. Resistance to this semi-synthetic glycopeptide is not readily developed in vitro.
Assuntos
Antibacterianos/farmacologia , Glicopeptídeos/farmacologia , Staphylococcus/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Teicoplanina/farmacologia , Vancomicina/farmacologiaRESUMO
Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC(50)=8.2 microM; 44, IC(50)=6.6 microM; 35e(2), IC(50)=1 microM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC=4-16 microg/mL; Klebsiella pneumoniae, MIC=8 microg/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED(50)=4.8 mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules.
Assuntos
Diamino Aminoácidos/química , Diamino Aminoácidos/farmacologia , Animais , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/crescimento & desenvolvimento , Camundongos , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Conformação MolecularRESUMO
Combinatorial libraries of N-acylated 5-(S)-aminomethyloxazolidinone derivatives of S-oxide and S,S-dioxide tetrahydro-4(2H)-thiopyranyl and thiomorpholine phenyloxazolidinone series have been synthesized on a solid phase and evaluated for antimicrobial activity. Several novel potent leads have been identified, including orally active oxazolidinones with enhanced activity against respiratory tract infection pathogens Haemophilus influenzae and Moraxella catarrhalis.
Assuntos
Antibacterianos/farmacocinética , Haemophilus influenzae/efeitos dos fármacos , Moraxella catarrhalis/efeitos dos fármacos , Morfolinas/química , Oxazolidinonas/farmacocinética , Óxidos/química , Compostos de Oxigênio/farmacocinética , Animais , Antibacterianos/administração & dosagem , Disponibilidade Biológica , Técnicas de Química Combinatória , Infecções por Haemophilus/microbiologia , Metabolismo dos Lipídeos , Masculino , Testes de Sensibilidade Microbiana , Infecções por Moraxellaceae/microbiologia , Oxazolidinonas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Antimicrobial compounds incorporating oxazolidinone and quinolone pharmacophore substructures have been synthesized and evaluated. Representative analogues 2, 5, and 6 display an improved potency versus linezolid against gram-positive and fastidious gram-negative pathogens. The compounds are also active against linezolid- and ciprofloxacin-resistant Staphylococcus aureus and Enterococcus faecium strains. The MOA for these new antimicrobials is consistent with a combination of protein synthesis and gyrase A/topoisomerase IV inhibition, with a structure-dependent degree of the contribution from each inhibitory mechanism.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Acetamidas/farmacologia , Antibacterianos/química , Ciprofloxacina/farmacologia , DNA Topoisomerase IV/antagonistas & inibidores , Farmacorresistência Bacteriana , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Linezolida , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazolidinonas/química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
Thiazole peptide GE2270 A (1) possesses potent antimicrobial activity against many gram-positive pathogens, including methicillin resistant Staphylococcus aureus (S. aureus, MRSA; MIC(90)=0.06 microg/mL) and vancomycin resistant Enterococcus spp. (VRE; MIC(90)=0.03 microg/mL); however its poor aqueous solubility has prohibited its development for the clinical treatment of infections. An integrated combinatorial and medicinal chemistry program was employed to identify derivatives of 1 that retain activity but possess greatly enhanced aqueous solubility.
Assuntos
Antibacterianos/síntese química , Produtos Biológicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/síntese química , Peptídeos , Tiazóis/química , Tiazóis/síntese química , Antibacterianos/química , Produtos Biológicos/química , Técnicas de Química Combinatória , Testes de Sensibilidade MicrobianaRESUMO
Negamycin 1 is a bactericidal antibiotic with activity against Gram-negative bacteria, and served as a template in an antibiotic discovery program. An orthogonally protected beta-amino acid derivative 3a was synthesized and used in parallel synthesis of negamycin derivatives on solid support. This advanced intermediate was also used for N- and C-terminal modifications using solution-phase methodologies. The N-terminal modifications have resulted in the identification of active analogues, whereas the C-terminal modifications resulted in complete loss of antibacterial activity. The N-methyl negamycin analogue, 19a, inhibits protein synthesis (IC(50)=2.3 microM), has antibacterial activity (Escherichia coli, MIC=16 microgram/mL), and is efficacious in an E. coli murine septicemia model (ED(50)=16.3mg/kg).
Assuntos
Diamino Aminoácidos/química , Diamino Aminoácidos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Animais , Bactérias/efeitos dos fármacos , Proteínas de Bactérias/biossíntese , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Hidrazinas/química , Indicadores e Reagentes , Camundongos , Testes de Sensibilidade Microbiana , Conformação Molecular , Inibidores da Síntese de Proteínas/síntese química , Inibidores da Síntese de Proteínas/farmacologia , Sepse/tratamento farmacológico , Sepse/microbiologiaRESUMO
Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P(1)' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P(1)' site. Compounds with MICs of