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1.
BMC Infect Dis ; 14: 16, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24405766

RESUMO

BACKGROUND: A limitation of both culture-based and molecular methods of screening for staphylococcal infection is that current tests determine only the presence or absence of colonization with no information on the colonizing strain type. A technique that couples polymerase chain reaction to mass spectrometry (PCR/ESI-MS) has recently been developed and an assay validated to identify and genotype S. aureus and coagulase-negative staphylococci (CoNS). METHODS: This study was conducted to determine the rates, risk factors, and molecular genotypes of colonizing Staphylococcus aureus in adult patients presenting to an inner-city academic emergency department. Participants completed a structured questionnaire to assess hospital and community risks for infection with methicillin-resistant S. aureus (MRSA). Nasal swabs were analyzed by PCR/ESI-MS to identify and genotype S. aureus and CoNS. RESULTS: Of 200 patients evaluated, 59 were colonized with S. aureus; 27 of these were methicillin-resistant strains. Twenty-four of the 59 S. aureus carriers were co-colonized with a CoNS and 140 of the 200 patients were colonized exclusively with CoNS. The molecular genotypes of the 59 S. aureus strains were diverse; 21 unique molecular genotypes belonging to seven major clonal complexes were identified. Eighty-five of 200 patients carried strains with high-level mupirocin resistance. Of these eighty-five participants, 4 were colonized exclusively with S. aureus, 16 were co-colonized with S. aureus and CoNS, and 65 were colonized exclusively with CoNS. CONCLUSION: The prevalence of S. aureus and methicillin-resistant S. aureus colonization in a random sample of patients seeking care in Emergency Department was 29.5% and 13.5%, respectively. A substantial fraction of the S. aureus-colonized patients were co-colonized with CoNS and high-level mupirocin-resistant CoNS. Determining the molecular genotype of S. aureus during intake screening may prove valuable in the future if certain molecular genotypes become associated with increased infection risk.


Assuntos
Infecções Estafilocócicas/diagnóstico , Staphylococcus aureus/genética , Adolescente , Adulto , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Maryland/epidemiologia , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pessoa de Meia-Idade , Mupirocina , Nariz/microbiologia , Reação em Cadeia da Polimerase/métodos , Prevalência , Estudos Prospectivos , Fatores de Risco , Espectrometria de Massas por Ionização por Electrospray , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Adulto Jovem
2.
J Clin Microbiol ; 50(7): 2529-30, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22518857

RESUMO

We describe the application of PCR and electrospray-ionization with mass spectrometry (PCR/ESI-MS) to culture-negative bronchoalveolar lavage (BAL) fluid in order to identify septate hyphae noted by Gomori methenamine silver (GMS) staining of the fluid that was obtained from an immunocompromised woman with neutropenia following induction chemotherapy for treatment of acute myelogenous leukemia (AML). The patient was treated with empirical antifungal therapy, including intrathecal amphotericin B, while results of fungal cultures were pending. Ultimately, Aspergillus terreus, an amphotericin-resistant mold, was cultured from bilateral brain abscesses. PCR/ESI-MS correctly identified the mold.


Assuntos
Aspergilose/diagnóstico , Aspergillus/isolamento & purificação , Líquido da Lavagem Broncoalveolar/microbiologia , Reação em Cadeia da Polimerase/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Antifúngicos/administração & dosagem , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Aspergillus/classificação , Aspergillus/genética , DNA Fúngico/química , DNA Fúngico/genética , Feminino , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neoplasias/complicações , Análise de Sequência de DNA
3.
J Clin Microbiol ; 50(6): 2018-25, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22442313

RESUMO

A pneumococcal serotyping/genotyping system (PSGS) was developed based upon targeted PCR, followed by electrospray ionization mass spectrometry and amplicon base composition analysis. Eight multiplex PCRs, 32 targeting serotype-determining capsular biosynthetic loci, and 8 targeting multilocus sequence typing (MLST) loci were employed for each of 229 highly diverse Streptococcus pneumoniae isolates. The most powerful aspect of the PSGS system was the identification of capsular serotypes accounting for the majority of invasive and carried pneumococcal strains. Altogether, 45 different serotypes or serogroups were correctly predicted among the 196 resolvable isolates, with only 2 unexpected negative results. All 33 isolates that represented 23 serotypes not included in the PSGS yielded negative serotyping results. A genotyping database was constructed using the base compositions of 65- to 100-bp sections of MLST alleles compiled within http://www.mlst.net. From this database, one or more MLST sequence types (STs) that comprised a PSGS genotype were identified. The end result of more PSGS genotypes (163) than conventional STs actually tested (155) was primarily due to amplification failures of 1 to 3 targets. In many instances, the PSGS genotype could provide resolution of single- and double-locus variants. This molecular serotyping/genotyping scheme is well suited to rapid characterization of large sets of pneumococcal isolates.


Assuntos
Técnicas de Tipagem Bacteriana/métodos , Reação em Cadeia da Polimerase/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Streptococcus pneumoniae/classificação , Streptococcus pneumoniae/genética , DNA Bacteriano/genética , Genótipo , Humanos
4.
J Med Chem ; 50(10): 2352-69, 2007 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-17458946

RESUMO

A series of 2"-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit microM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.


Assuntos
Antibacterianos/síntese química , Paromomicina/análogos & derivados , Paromomicina/síntese química , RNA Ribossômico/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Éteres/síntese química , Éteres/química , Éteres/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Paromomicina/química , Paromomicina/farmacologia , Sepse/prevenção & controle , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
5.
J Med Chem ; 48(23): 7099-102, 2005 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-16279767

RESUMO

A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole 'hit' 1 with a KD approximately 100 microM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure-activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their KD for the RNA target.


Assuntos
Benzimidazóis/química , Hepacivirus/genética , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , RNA Viral/química , Ribossomos/efeitos dos fármacos , Sequência de Bases , Benzimidazóis/farmacologia , Benzimidazóis/toxicidade , Sítios de Ligação , Linhagem Celular , Bases de Dados Factuais , Hepacivirus/fisiologia , Humanos , Espectrometria de Massas , Dados de Sequência Molecular , Conformação de Ácido Nucleico , RNA Viral/metabolismo , Ribossomos/química , Ribossomos/metabolismo , Replicação Viral
7.
Artigo em Inglês | MEDLINE | ID: mdl-15043144

RESUMO

The electrophilic fluorination of 4-chloropyrrolo[2,3-d]pyrimidine (1) was studied culminating a 59% conversion of compound 1 to 4-chloro-5-fluoropyrrolo[2,3-d]pyrimidine (2) using Selectfluor. This transformation proceeded via the 4-chloro-5,6-dihydro-5-fluoro-6-hydroxypyrrolo[2,3-d]pyrimidine (3) in a 9:1 trans:cis ratio. The trans isomer of compound 3 was studied by 1H NMR and 19F NMR, and the 5-H tautomer (4) was observed as another intermediate. A modified Vorbruggen procedure of compound 2 and tetra-O-acetylribose gave 4-chloro-5-fluoro-7-(2,3,5,-tri-O-benzoyl-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (6) in a 65% yield. Treatment of compound 6 with ammonia (l) in dioxane gave 5-fluorotubercidin (7). No antibacterial activity was observed. An MTT assay (Promega) against Huh-7 liver cells, normal mouse spleen cells stimulated with Con A (a T-cell mitogen), and normal mouse spleen stimulated with LPS (a B-cell mitogen) showed no significant toxicity. Increased activity of 7 over tubercidin was observed against L-1210 cells and toxicity in fibroblast cells was reduced.


Assuntos
Antibióticos Antineoplásicos/síntese química , Flúor/química , Tubercidina/análogos & derivados , Antibióticos Antineoplásicos/farmacologia , Cromatografia em Gel , Escherichia coli/efeitos dos fármacos , Genes Reporter , Espectroscopia de Ressonância Magnética , Biossíntese de Proteínas/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Tubercidina/síntese química
8.
Bioorg Med Chem Lett ; 13(19): 3253-6, 2003 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-12951103

RESUMO

A series of 2-piperidin-4-yl-benzimidazoles were synthesized and evaluated for antibacterial activities. Certain compounds inhibit bacterial growth with low micromolar minimal inhibitory concentration (MIC). These benzimidazoles are effective against both Gram-positive and Gram-negative bacteria of clinical importance, particularly enterococci, and represent a new class of potential antibacterial agents.


Assuntos
Antibacterianos/química , Benzimidazóis/química , Piperidinas/química , Antibacterianos/farmacologia , Benzimidazóis/farmacologia , Enterococcus/efeitos dos fármacos , Enterococcus/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana/métodos , Piperidinas/farmacologia
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