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2.
Ann N Y Acad Sci ; 1241: 71-81, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22191527

RESUMO

In 1951, the first reference to the antibacterial substance pleuromutilin was made in a paper published in the Proceedings of the National Academy of Sciences. Researchers had identified several species of the mold genus Pleurotus that inhibited the growth of Staphylococcus aureus. The elucidation of the structure in 1962 led to the initiation of a development program at Sandoz, which was followed by the approval of tiamulin in 1979 for use in veterinary medicine. Although in 2007 retapamulin became the first pleuromutilin approved for topical use in humans, it was not until 2011, exactly 60 years after the first mention of the class, that a pleuromutilin antibiotic, BC-3781, could be tested successfully in a clinical phase II trial for systemic use in patients. This review will discuss key aspects of this antibacterial class and provide some insight into the question of why it took half a century to develop a systemic pleuromutilin for human use.


Assuntos
Antibacterianos/uso terapêutico , Antibacterianos/química , Antibacterianos/história , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/história , Diterpenos/química , Diterpenos/história , Diterpenos/uso terapêutico , Descoberta de Drogas/história , Farmacorresistência Bacteriana , História do Século XX , História do Século XXI , Humanos , Compostos Policíclicos , Relação Estrutura-Atividade , Pleuromutilinas
3.
Curr Opin Investig Drugs ; 11(2): 182-91, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20112168

RESUMO

Pleuromutilins were discovered as natural-product antibiotics in 1950. Tiamulin was the first pleuromutilin compound to be approved for veterinary use in 1979, followed by valnemulin in 1999. It was not until 2007 that retapamulin became the first pleuromutilin approved for use in humans. However, retapamulin is limited to topical application. Recent advances in lead optimization have led to the synthesis of pleuromutilins that combine potent antibacterial activity with favorable pharmaceutical properties, making these compounds suitable for oral and intravenous delivery. Most pleuromutilins have an antibacterial spectrum that spans the common pathogens involved in both skin and respiratory tract infections. Two new pleuromutilins, BC-3205 and BC-7013 (both Nabriva Therapeutics AG), have entered clinical trials. In this review, the key properties of pleuromutilin derivatives, designed primarily through modifications at the C(14) side chain, are presented, and the potential of these compounds in systemic therapy in humans is discussed.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/história , Ensaios Clínicos como Assunto , Diterpenos/administração & dosagem , Diterpenos/história , Diterpenos/farmacologia , História do Século XX , História do Século XXI , Humanos , Testes de Sensibilidade Microbiana , Compostos Policíclicos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/microbiologia , Relação Estrutura-Atividade , Pleuromutilinas
4.
J Biol Chem ; 281(15): 10035-41, 2006 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-16459335

RESUMO

Emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created challenges in treatment of nosocomial infections. The recent clinical emergence of vancomycin-resistant MRSA is a new disconcerting chapter in the evolution of these strains. S. aureus normally produces four PBPs, which are susceptible to modification by beta-lactam antibiotics, an event that leads to bacterial death. The gene product of mecA from MRSA is a penicillin-binding protein (PBP) designated PBP 2a. PBP 2a is refractory to the action of all commercially available beta-lactam antibiotics. Furthermore, PBP 2a is capable of taking over the functions of the other PBPs of S. aureus in the face of the challenge by beta-lactam antibiotics. Three cephalosporins (compounds 1-3) have been studied herein, which show antibacterial activities against MRSA, including the clinically important vancomycin-resistant strains. These cephalosporins exhibit substantially smaller dissociation constants for the preacylation complex compared with the case of typical cephalosporins, but their pseudo-second-order rate constants for encounter with PBP 2a (k(2)/K(s)) are not very large (< or =200 m(-1) s(-1)). It is documented herein that these cephalosporins facilitate a conformational change in PBP 2a, a process that is enhanced in the presence of a synthetic surrogate for cell wall, resulting in increases in the k(2)/K(s) parameter and in more facile enzyme inhibition. These findings argue that the novel cephalosporins are able to co-opt interactions between PBP 2a and the cell wall in gaining access to the active site in the inhibition process, a set of events that leads to effective inhibition of PBP 2a and the attendant killing of the MRSA strains.


Assuntos
Cefalosporinas/farmacologia , Farmacorresistência Bacteriana , Meticilina/farmacologia , Staphylococcus aureus/metabolismo , Vancomicina/farmacologia , Antibacterianos/farmacologia , Sítios de Ligação , Parede Celular/metabolismo , Dicroísmo Circular , Clonagem Molecular , Eletroforese em Gel de Poliacrilamida , Cinética , Resistência a Meticilina , Modelos Químicos , Conformação Molecular , Proteínas de Ligação às Penicilinas/química , Ligação Proteica , Conformação Proteica , Staphylococcus aureus/efeitos dos fármacos , Fatores de Tempo , Raios Ultravioleta
5.
Mol Microbiol ; 53(5): 1515-27, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15387826

RESUMO

The capacity of pathogens to cause disease depends strictly on the regulated expression of their virulence factors. In this study, we demonstrate that the untranslated mRNA of the recently described streptococcal pleiotropic effect locus (pel), which incidentally contains sagA, the structural gene for streptolysin S, is an effector of virulence factor expression in group A beta-haemolytic streptococci (GAS). Our data suggest that the regulation by pel RNA occurs at both transcriptional (e.g. emm, sic, nga) and post-transcriptional (e.g. SpeB) levels. We could exclude the possibility that the pel phenotype was linked to a polar effect on downstream genes (sagB-I). Remarkably, the RNA effector is regulated in a growth phase-dependent fashion and we provide evidence that pel RNA expression is induced by conditioned media.


Assuntos
Proteínas de Bactérias/biossíntese , Regulação Bacteriana da Expressão Gênica , RNA Bacteriano/metabolismo , Streptococcus pyogenes/metabolismo , Regiões não Traduzidas/metabolismo , Fatores de Virulência/biossíntese , Proteínas de Bactérias/genética , Meios de Cultivo Condicionados , Fenótipo , Streptococcus pyogenes/genética , Streptococcus pyogenes/patogenicidade , Transcrição Gênica , Fatores de Virulência/genética
6.
J Infect Dis ; 189(2): 328-38, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14722899

RESUMO

Penicillin and vancomycin induce a lytic response in Streptococcus pneumoniae that requires the N-acetylmuramyl-l-alanine amidase LytA. We show that clinical isolates of pneumococci of capsular serotypes 1, 4, 6B, and 23F were generally less lytic to penicillin than pneumococci of serotypes 14 and 3. In addition, most 9V isolates were less lytic to vancomycin, compared with isolates of other serotypes. Parent-mutant pairs expressing and not expressing capsular serotypes 2, 4, and 9V were compared for antibiotic-induced lysis. The nonencapsulated variants were considerably more lytic after beta-lactam and/or vancomycin treatment, and antibiotic tolerance was seen only in the context of capsule expression. Conversion from a nonlytic to a lytic phenotype, after loss of capsule expression, required an intact lytA autolysin gene. Exogenous addition of purified LytA gave a lower lytic response in capsulated strains, compared with that in nonencapsulated mutants. Spontaneous autolysis in stationary phase also was negatively affected by capsule expression in an autolysin-dependent manner. Long-term starvation in the stationary phase of the vancomycin- and penicillin-tolerant isolate I95 yielded nonencapsulated mutants that had lost antibiotic tolerance and were lytic to penicillin and vancomycin. The 9V capsular locus of I95 and one of these stationary phase-selected mutants were completely sequenced. The only difference found was a 1-bp frameshift deletion in the cps9vE gene of the lytic mutant, encoding a uridine diphosphate-glucosyl-1-phosphate transferase. Two additional independently isolated lytic mutants of I95 from the stationary phase also contained mutations in the same region of cps9vE, which identified it as a mutational hot spot. This report demonstrates that capsular polysaccharides negatively influence the lytic process and contribute to antibiotic tolerance in clinical isolates of pneumococci.


Assuntos
Antibacterianos/farmacologia , Cápsulas Bacterianas/fisiologia , Bacteriólise , Streptococcus pneumoniae/efeitos dos fármacos , Farmacorresistência Bacteriana , Enzimas/fisiologia , N-Acetil-Muramil-L-Alanina Amidase/fisiologia , Sorotipagem , Streptococcus pneumoniae/fisiologia
7.
J Infect Dis ; 188(10): 1578-86, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14624385

RESUMO

We determined the toxin-gene profiles of 239 endemic, invasive group A streptococcal (GAS) isolates that circulated, within a 5-year period, in European university hospitals. Profiling was performed by use of multiplex polymerase chain reaction that screened for 9 streptococcal pyrogenic exotoxins (speA, speB, speC, speF, speG, speH, speJ, ssa, and smeZ). Analysis revealed that invasive GAS isolates do not share a common toxin-gene profile. Although all emm types were characterized by several different toxin-gene profiles, a predominance of 1 or 2 toxin-gene profiles could be observed, reflecting that a few invasive clones have spread successfully throughout the world. Remarkably, statistical pair-wise analysis of individual toxin genes revealed that strains that did not share the predominant profile still showed a nonrandom distribution of key toxin genes characteristic of the specific emm type. This could indicate that M proteins function, directly or indirectly, as barriers for horizontal gene exchange.


Assuntos
Antígenos de Bactérias , Proteínas da Membrana Bacteriana Externa/genética , Toxinas Bacterianas/genética , Proteínas de Transporte/genética , Streptococcus pyogenes/genética , Proteínas da Membrana Bacteriana Externa/isolamento & purificação , Toxinas Bacterianas/química , Proteínas de Transporte/isolamento & purificação , Infecção Hospitalar/microbiologia , DNA Bacteriano/química , DNA Bacteriano/genética , Europa (Continente) , Variação Genética , Humanos , Reação em Cadeia da Polimerase , Streptococcus pyogenes/classificação , Streptococcus pyogenes/isolamento & purificação
8.
J Clin Microbiol ; 41(11): 4941-9, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14605121

RESUMO

As part of a national surveillance program on invasive group A streptococci (GAS), isolates that caused specific manifestations of invasive GAS disease in The Netherlands were collected between 1992 and 1996. These site-specific GAS infections involved meningitis, arthritis, necrotizing fasciitis, and puerperal sepsis. An evaluation was performed to determine whether GAS virulence factors correlate with these different disease manifestations. PCRs were developed to detect 9 genes encoding exotoxins and 12 genes encoding fibronectin binding proteins. The genetic backgrounds of all isolates were determined by M genotyping and pulsed-field gel electrophoresis (PFGE) analysis. The predominant M types included M1, M2, M3, M4, M6, M9, M12, and M28. Most M types were associated with all manifestations of GAS disease. However, M2 was found exclusively in patients with puerperal sepsis, M6 predominated in patients with meningitis, and M12 predominated in patients with GAS arthritis. While characteristic gene profiles were detected in most M types, the resolution of detection of different gene profiles within M genotypes was enhanced by PFGE analysis, which clearly demonstrated the existence of some clonal lineages among invasive GAS isolates in The Netherlands. M1 isolates comprised a single clone carrying highly mitogenic toxin genes (speA, smeZ) and were associated with toxic shock-like syndrome. Toxin profiles were highly conserved among the most virulent strains, such as M1 and M3.


Assuntos
Infecções Estreptocócicas/epidemiologia , Streptococcus pyogenes/genética , Streptococcus pyogenes/patogenicidade , Artrite/epidemiologia , Artrite/microbiologia , Sequência de Bases , Primers do DNA , Eletroforese em Gel de Campo Pulsado , Feminino , Genes Bacterianos , Genótipo , Humanos , Meningites Bacterianas/epidemiologia , Países Baixos/epidemiologia , Filogenia , Transtornos Puerperais/epidemiologia , Transtornos Puerperais/microbiologia , Infecções Estreptocócicas/classificação , Infecções Estreptocócicas/complicações , Streptococcus pyogenes/classificação , Virulência
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