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[PMID]:28749938
[Au] Autor:Lai GC; Cho H; Bernhardt TG
[Ad] Endereço:Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, United States of America.
[Ti] Título:The mecillinam resistome reveals a role for peptidoglycan endopeptidases in stimulating cell wall synthesis in Escherichia coli.
[So] Source:PLoS Genet;13(7):e1006934, 2017 Jul.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bacterial cells are typically surrounded by an net-like macromolecule called the cell wall constructed from the heteropolymer peptidoglycan (PG). Biogenesis of this matrix is the target of penicillin and related beta-lactams. These drugs inhibit the transpeptidase activity of PG synthases called penicillin-binding proteins (PBPs), preventing the crosslinking of nascent wall material into the existing network. The beta-lactam mecillinam specifically targets the PBP2 enzyme in the cell elongation machinery of Escherichia coli. Low-throughput selections for mecillinam resistance have historically been useful in defining mechanisms involved in cell wall biogenesis and the killing activity of beta-lactam antibiotics. Here, we used transposon-sequencing (Tn-Seq) as a high-throughput method to identify nearly all mecillinam resistance loci in the E. coli genome, providing a comprehensive resource for uncovering new mechanisms underlying PG assembly and drug resistance. Induction of the stringent response or the Rcs envelope stress response has been previously implicated in mecillinam resistance. We therefore also performed the Tn-Seq analysis in mutants defective for these responses in addition to wild-type cells. Thus, the utility of the dataset was greatly enhanced by determining the stress response dependence of each resistance locus in the resistome. Reasoning that stress response-independent resistance loci are those most likely to identify direct modulators of cell wall biogenesis, we focused our downstream analysis on this subset of the resistome. Characterization of one of these alleles led to the surprising discovery that the overproduction of endopeptidase enzymes that cleave crosslinks in the cell wall promotes mecillinam resistance by stimulating PG synthesis by a subset of PBPs. Our analysis of this activation mechanism suggests that, contrary to the prevailing view in the field, PG synthases and PG cleaving enzymes need not function in multi-enzyme complexes to expand the cell wall matrix.
[Mh] Termos MeSH primário: Parede Celular/genética
Farmacorresistência Bacteriana/genética
Endopeptidases/biossíntese
Peptidoglicano/biossíntese
[Mh] Termos MeSH secundário: Andinocilina/farmacologia
Parede Celular/metabolismo
Endopeptidases/efeitos dos fármacos
Escherichia coli/efeitos dos fármacos
Escherichia coli/genética
Proteínas de Escherichia coli/biossíntese
Proteínas de Escherichia coli/genética
Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos
Genoma Bacteriano/efeitos dos fármacos
Proteínas de Ligação às Penicilinas/biossíntese
Proteínas de Ligação às Penicilinas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Escherichia coli Proteins); 0 (Penicillin-Binding Proteins); 0 (Peptidoglycan); 0 (peptidoglycan endopeptidase); EC 2.4.1.129 (MrdA protein, E coli); EC 3.4.- (Endopeptidases); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006934


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[PMID]:27806687
[Au] Autor:O'Kelly F; Kavanagh S; Manecksha R; Thornhill J; Fennell JP
[Ad] Endereço:Department of Urological Surgery, AMNCH, Tallaght Hospital, Dublin 24, Ireland.
[Ti] Título:Characteristics of gram-negative urinary tract infections caused by extended spectrum beta lactamases: pivmecillinam as a treatment option within South Dublin, Ireland.
[So] Source:BMC Infect Dis;16(1):620, 2016 Nov 03.
[Is] ISSN:1471-2334
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The prevalence of urinary tract infections (UTIs) caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae is increasing and the therapeutic options are limited, especially in primary care. Recent indications have suggested pivmecillinam to be a suitable option. This pilot study aimed to assess the viability of pivmecillinam as a therapeutic option in a Dublin cohort of mixed community and healthcare origin. METHODS: A prospective measurement of mean and fractional inhibitory concentrations of antibiotic use in 95 patients diagnosed with UTI caused by ESBL-producing Enterobacteriaceae was carried out. 36 % patients were from general practice, 40 % were admitted to hospital within south Dublin, and 25 % samples arose from nursing homes. EUCAST breakpoints were used to determine if an isolate was sensitive or resistant to antibiotic agents. RESULTS: Sixty-nine percent of patients (N = 66) with urinary ESBL isolates were female. The mean age of females was 66 years compared with a mean age of 74 years for males. Thirty-six percent of isolates originated from primary care, hospital inpatients (26 %), and nursing homes (24 %). The vast majority of ESBL isolates were E. coli (80 %). The E tests for mecillinam and co-amoxiclav had concentration ranges from 0.16 mg/L up to 256 mg/L. The mean inhibitory concentration (MIC) of mecillinam ranged from 0.25 to 256 mg/L, while co-amoxiclav MICs ranged from 6 to 256 mg/L. The percentage of isolates resistant to mecillinam and co-amoxiclav was found to be 5.26 and 94.74 % respectively. CONCLUSIONS: This is the first study exploring the use of pivmecillinam in an Irish cohort and has demonstrated that its use in conjunction with or without co-amoxiclav is an appropriate and useful treatment for urinary tract infections caused by ESBL-producing organisms.
[Mh] Termos MeSH primário: Andinocilina Pivoxil/uso terapêutico
Antibacterianos/uso terapêutico
Infecções por Escherichia coli/tratamento farmacológico
Infecções por Klebsiella/tratamento farmacológico
Infecções Urinárias/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso
Andinocilina/farmacologia
Andinocilina/uso terapêutico
Andinocilina Pivoxil/farmacologia
Combinação Amoxicilina e Clavulanato de Potássio/farmacologia
Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico
Antibacterianos/farmacologia
Farmacorresistência Bacteriana
Escherichia coli/efeitos dos fármacos
Escherichia coli/metabolismo
Escherichia coli/fisiologia
Infecções por Escherichia coli/microbiologia
Feminino
Medicina Geral
Bactérias Gram-Negativas/efeitos dos fármacos
Bactérias Gram-Negativas/metabolismo
Bactérias Gram-Negativas/fisiologia
Infecções por Bactérias Gram-Negativas/tratamento farmacológico
Infecções por Bactérias Gram-Negativas/microbiologia
Hospitalização
Hospitais
Seres Humanos
Irlanda
Infecções por Klebsiella/microbiologia
Klebsiella pneumoniae/efeitos dos fármacos
Klebsiella pneumoniae/metabolismo
Klebsiella pneumoniae/fisiologia
Masculino
Testes de Sensibilidade Microbiana
Casas de Saúde
Projetos Piloto
Prevalência
Estudos Prospectivos
Fatores de Risco
Infecções Urinárias/microbiologia
beta-Lactamases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 1WAM1OQ30B (Amdinocillin Pivoxil); 74469-00-4 (Amoxicillin-Potassium Clavulanate Combination); EC 3.5.2.6 (beta-Lactamases); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161104
[St] Status:MEDLINE


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[PMID]:27412057
[Au] Autor:Chen YT; Ahmad Murad K; Ng LS; Seah JT; Park JJ; Tan TY
[Ad] Endereço:Department of Laboratory Medicine, Changi General Hospital, Singapore.
[Ti] Título:In Vitro Efficacy of Six Alternative Antibiotics against Multidrug Resistant Escherichia Coli and Klebsiella Pneumoniae from Urinary Tract Infections.
[So] Source:Ann Acad Med Singapore;45(6):245-50, 2016 Jun.
[Is] ISSN:0304-4602
[Cp] País de publicação:Singapore
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Increasing resistance in Escherichia coli and Klebsiella pneumoniae to firstline antibiotics makes therapeutic options for urinary tract infections (UTIs) challenging. This study investigated the in vitro efficacies of 6 antibiotics against multidrug resistant (MDR) uropathogens. MATERIALS AND METHODS: Minimum inhibitory concentrations to ceftibuten, cefpodoxime, fosfomycin, mecillinam, temocillin, and trimethoprim were determined against 155 MDR-isolates of E. coli and K. pneumoniae. The presence of extended-spectrum beta-lactamases (ESBL) and plasmid-borne AmpC enzymes was determined by phenotypic testing with genotyping performed by multiplex polymerase chain reaction. RESULTS: Temocillin demonstrated highest susceptibility rates for both E. coli (95%) and K. pneumoniae (95%) when breakpoints for uncomplicated UTIs were applied; however, temocillin susceptibility was substantially lower when "systemic infection" breakpoints were used. Fosfomycin demonstrated the best in vitro efficacy of the orally available agents, with 78% and 69% of E. coli and K. pneumoniae isolates susceptible, respectively. The next most effective antibiotics were ceftibuten (45%) and mecillinam (32%). ESBL and ampC genes were present in 47 (30%) and 59 (38%) isolates. CONCLUSION: This study demonstrated few oral therapeutic options for MDR-uropathogens, with fosfomycin demonstrating the best in vitro activity.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Escherichia coli/efeitos dos fármacos
Klebsiella pneumoniae/efeitos dos fármacos
Infecções Urinárias/microbiologia
[Mh] Termos MeSH secundário: Andinocilina/farmacologia
Proteínas de Bactérias/genética
Ceftizoxima/análogos & derivados
Ceftizoxima/farmacologia
Cefalosporinas/farmacologia
Farmacorresistência Bacteriana Múltipla/genética
Escherichia coli/genética
Infecções por Escherichia coli/microbiologia
Fosfomicina/farmacologia
Genótipo
Seres Humanos
Técnicas In Vitro
Infecções por Klebsiella/microbiologia
Klebsiella pneumoniae/genética
Testes de Sensibilidade Microbiana
Reação em Cadeia da Polimerase Multiplex
Penicilinas/farmacologia
Singapura
Trimetoprima/farmacologia
beta-Lactamases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Cephalosporins); 0 (Penicillins); 03QB156W6I (temocillin); 2N81MY12TE (Fosfomycin); 7R4F94TVGY (cefpodoxime); AN164J8Y0X (Trimethoprim); C43C467DPE (Ceftizoxime); EC 3.5.2.6 (AmpC beta-lactamases); EC 3.5.2.6 (beta-Lactamases); IW71N46B4Y (ceftibuten); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170214
[Lr] Data última revisão:
170214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160715
[St] Status:MEDLINE


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[PMID]:27330062
[Au] Autor:Doumith M; Mushtaq S; Livermore DM; Woodford N
[Ad] Endereço:National Infection Service, Public Health England, London NW9 5EQ, UK michel.doumith@phe.gov.uk.
[Ti] Título:New insights into the regulatory pathways associated with the activation of the stringent response in bacterial resistance to the PBP2-targeted antibiotics, mecillinam and OP0595/RG6080.
[So] Source:J Antimicrob Chemother;71(10):2810-4, 2016 Oct.
[Is] ISSN:1460-2091
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: The diazabicyclooctane ß-lactamase inhibitor OP0595 (RG6080) also acts as an antibiotic, targeting PBP2 in Enterobacteriaceae, but this activity is vulnerable to mutational resistance. We used WGS to investigate the basis of this resistance. METHODS: Twenty OP0595-selected mutants, comprising four derived from each of five different Escherichia coli strains, were sequenced on Illumina HiSeq. Reads from each mutant were mapped to the assembled genome of the corresponding parent. A variant-calling file generated with Samtools was parsed to determine genetic alterations. RESULTS: Besides OP0595, the mutants consistently showed decreased susceptibility to mecillinam, which likewise targets PBP2, and grew as stable round forms in the presence of subinhibitory concentrations of OP0595. Among the 20 mutants, 18 had alterations in genes encoding tRNA synthase and modification functions liable to induce expression of the RpoS sigma factor through activation of the stringent response or had mutations suppressing inactivators of RpoS or the stringent response signal-degrading enzyme, SpoT. TolB was inactivated in one mutant: this activates RcsBC regulation and was previously associated with mecillinam resistance. The mechanism of resistance remained unidentified in one mutant. Both the RpoS and RcsBC systems regulate genes of cell division, including ftsAQZ that can compensate for loss or inhibition of PBP2, allowing survival of the challenged bacteria as stable round forms, as seen. CONCLUSIONS: WGS identified the global stringent response signal, entailing induction of RpoS, as the main mediator of mutational resistance to OP0595 in E. coli.
[Mh] Termos MeSH primário: Andinocilina/farmacologia
Antibacterianos/farmacologia
Compostos Azabicíclicos/farmacologia
Farmacorresistência Bacteriana Múltipla/genética
Proteínas de Escherichia coli/antagonistas & inibidores
Escherichia coli/efeitos dos fármacos
Regulação Bacteriana da Expressão Gênica
Lactamas/farmacologia
Proteínas de Ligação às Penicilinas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Andinocilina/metabolismo
Compostos Azabicíclicos/metabolismo
Proteínas de Bactérias/genética
Escherichia coli/citologia
Escherichia coli/genética
Escherichia coli/metabolismo
Variação Genética
Genoma Bacteriano
Sequenciamento de Nucleotídeos em Larga Escala
Lactamas/metabolismo
Microscopia Eletrônica de Transmissão
Mutação
Fator sigma/genética
Inibidores de beta-Lactamases/metabolismo
Inibidores de beta-Lactamases/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Azabicyclo Compounds); 0 (Bacterial Proteins); 0 (Escherichia coli Proteins); 0 (Lactams); 0 (OP0595); 0 (Penicillin-Binding Proteins); 0 (Sigma Factor); 0 (beta-Lactamase Inhibitors); 0 (sigma factor KatF protein, Bacteria); EC 2.4.1.129 (MrdA protein, E coli); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160623
[St] Status:MEDLINE
[do] DOI:10.1093/jac/dkw230


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[PMID]:27165786
[Au] Autor:Nilsen E; Aasterød M; Hustad PS; Olsen AO
[Ad] Endereço:Department of Medical Microbiology, More and Romsdal Health Trust, Molde, Norway einar.nilsen@helse-mr.no.
[Ti] Título:Mecillinam against genital Chlamydia trachomatis infection: a small-scale proof-of-concept study shows a low cure rate.
[So] Source:J Antimicrob Chemother;71(8):2270-2, 2016 Aug.
[Is] ISSN:1460-2091
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Mecillinam is highly active in vitro against Chlamydia spp. We aimed to determine whether mecillinam should be evaluated further as treatment for genital Chlamydia trachomatis infection. PATIENTS AND METHODS: The study was conducted at an open-access clinic for sexually transmitted infections in Oslo, Norway. We planned to include 50 patients. Participants were asymptomatic, heterosexual male patients with a first-void urine sample found to be positive for C. trachomatis by PCR. Treatment consisted of 400 mg of pivmecillinam hydrochloride three times a day for 7 days. A test-of-cure sample, a medication diary and a questionnaire were returned by the participants, and they were used to evaluate treatment outcome, compliance, risk of reinfection and theoretical percentage of time above MIC (t/MIC %). The study was registered in Eudra-CT (no. 2013-002379-179) and clinicaltrals.gov (NCT02083276). RESULTS: The study was discontinued after including 20 patients, due to a high failure rate. Only two of the 17 participants who delivered a test-of-cure sample were cured. Three participants reported condomless sex before the follow-up sample. When the average or most favourable pharmacokinetics (PK)/pharmacodynamics (PD) reported from other studies were applied in a theoretical model, the estimated t/MIC % was above 50% for all of the 15 participants returning a medication diary. Using the least favourable PK/PD, no participant had t/MIC % of >36%. The mean dose interval was 8 h 36 min (standard deviation 3 h 12 min). CONCLUSIONS: A low cure rate combined with uncertainty about intracellular availability and attained t/MIC % makes mecillinam an unattractive candidate for further evaluation as treatment for genital C. trachomatis infection.
[Mh] Termos MeSH primário: Andinocilina/administração & dosagem
Anti-Infecciosos Urinários/administração & dosagem
Chlamydia trachomatis/efeitos dos fármacos
Linfogranuloma Venéreo/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Seres Humanos
Masculino
Meia-Idade
Noruega
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Infective Agents, Urinary); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160512
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1093/jac/dkw134


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[PMID]:26908573
[Au] Autor:Delhaye A; Collet JF; Laloux G
[Ad] Endereço:de Duve Institute, Université catholique de Louvain, Brussels, Belgium WELBIO, Brussels, Belgium.
[Ti] Título:Fine-Tuning of the Cpx Envelope Stress Response Is Required for Cell Wall Homeostasis in Escherichia coli.
[So] Source:MBio;7(1):e00047-16, 2016 Feb 23.
[Is] ISSN:2150-7511
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: The envelope of Gram-negative bacteria is an essential compartment that constitutes a protective and permeability barrier between the cell and its environment. The envelope also hosts the cell wall, a mesh-like structure made of peptidoglycan (PG) that determines cell shape and provides osmotic protection. Since the PG must grow and divide in a cell-cycle-synchronized manner, its synthesis and remodeling are tightly regulated. Here, we discovered that PG homeostasis is intimately linked to the levels of activation of the Cpx system, an envelope stress response system traditionally viewed as being involved in protein quality control in the envelope. We first show that Cpx is activated when PG integrity is challenged and that this activation provides protection to cells exposed to antibiotics inhibiting PG synthesis. By rerouting the outer membrane lipoprotein NlpE, a known Cpx activator, to a different envelope subcompartment, we managed to manipulate Cpx activation levels. We found that Cpx overactivation leads to aberrant cellular morphologies, to an increased sensitivity to ß-lactams, and to dramatic division and growth defects, consistent with a loss of PG homeostasis. Remarkably, these phenotypes were largely abrogated by the deletion of ldtD, a Cpx-induced gene involved in noncanonical PG cross-linkage, suggesting that this transpeptidase is an important link between PG homeostasis and the Cpx system. Altogether our data show that fine-tuning of an envelope quality control system constitutes an important layer of regulation of the highly organized cell wall structure. IMPORTANCE: The envelope of Gram-negative bacteria is essential for viability. First, it includes the cell wall, a continuous polymer of peptidoglycan (PG) that determines cell morphology and protects against osmotic stress. Moreover, the envelope constitutes a protective barrier between the cell interior and the environment. Therefore, mechanisms called envelope stress response systems (ESRS) exist to monitor and defend envelope integrity against harmful conditions. Cpx is a major ESRS that detects and manages the accumulation of misfolded proteins in the envelope of Escherichia coli. We found that this protein quality control system also plays a fundamental role in the regulation of PG assembly. Strikingly, the level of Cpx response is critical, as an excessive activation leads to phenotypes associated with a loss of cell wall integrity. Thus, by contributing to PG homeostasis, the Cpx system lies at the crossroads between key processes of bacterial life, including cell shape, growth, division, and antibiotic resistance.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Parede Celular/metabolismo
Proteínas de Escherichia coli/genética
Escherichia coli/metabolismo
Homeostase
Peptidoglicano/metabolismo
Proteínas Quinases/metabolismo
[Mh] Termos MeSH secundário: Andinocilina/farmacologia
Proteínas da Membrana Bacteriana Externa/genética
Proteínas de Bactérias/genética
Cefalexina/farmacologia
Escherichia coli/genética
Escherichia coli/crescimento & desenvolvimento
Escherichia coli/ultraestrutura
Proteínas de Escherichia coli/metabolismo
Regulação Bacteriana da Expressão Gênica
Lipoproteínas/genética
Lipoproteínas/metabolismo
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Fenótipo
Proteínas Quinases/genética
Estresse Fisiológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Outer Membrane Proteins); 0 (Bacterial Proteins); 0 (Escherichia coli Proteins); 0 (Lipoproteins); 0 (Membrane Proteins); 0 (NlpE protein, E coli); 0 (Peptidoglycan); 153554-07-5 (CpxR protein, Bacteria); EC 2.7.- (Protein Kinases); EC 2.7.3.- (CpxA protein, E coli); OBN7UDS42Y (Cephalexin); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160225
[St] Status:MEDLINE


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[PMID]:25845878
[Au] Autor:Kocaoglu O; Tsui HC; Winkler ME; Carlson EE
[Ad] Endereço:Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
[Ti] Título:Profiling of ß-lactam selectivity for penicillin-binding proteins in Streptococcus pneumoniae D39.
[So] Source:Antimicrob Agents Chemother;59(6):3548-55, 2015.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Selective fluorescent ß-lactam chemical probes enable the visualization of the transpeptidase activity of penicillin-binding proteins (PBPs) at different stages of bacterial cell division. To facilitate the development of new fluorescent probes for PBP imaging, we evaluated 20 commercially available ß-lactams for selective PBP inhibition in an unencapsulated derivative of the D39 strain of Streptococcus pneumoniae. Live cells were treated with ß-lactam antibiotics at different concentrations and subsequently incubated with Bocillin FL (Boc-FL; fluorescent penicillin) to saturate uninhibited PBPs. Fluorophore-labeled PBPs were visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fluorescence scanning. Among 20 compounds tested, carbapenems (doripenem and meropenem) were coselective for PBP1a, PBP2x, and PBP3, while six of the nine penicillin compounds were coselective for PBP2x and PBP3. In contrast, the seven cephalosporin compounds tested display variability in their PBP-binding profiles. Three cephalosporin compounds (cefoxitin, cephalexin, and cefsulodin) and the monobactam aztreonam exhibited selectivity for PBP3, while only cefuroxime (a cephalosporin) was selective for PBP2x. Treatment of S. pneumoniae cultures with a sublethal concentration of cefuroxime that inhibited 60% of PBP2x activity and less than 20% of the activity of other PBPs resulted in formation of elongated cells. In contrast, treatment of S. pneumoniae cultures with concentrations of aztreonam and cefoxitin that inhibited up to 70% of PBP3 activity and less than 30% of other PBPs resulted in no discernible morphological changes. Additionally, correlation of the MIC and IC50s for each PBP, with the exception of faropenem, amdinocillin (mecillinam), and 6-APA, suggests that pneumococcal growth inhibition is primarily due to the inhibition of PBP2x.
[Mh] Termos MeSH primário: Proteínas de Ligação às Penicilinas/metabolismo
Streptococcus pneumoniae/efeitos dos fármacos
Streptococcus pneumoniae/metabolismo
beta-Lactamas/farmacologia
[Mh] Termos MeSH secundário: Andinocilina/farmacologia
Antibacterianos/farmacologia
Carbapenêmicos/farmacologia
Cefalosporinas/farmacologia
Eletroforese em Gel de Poliacrilamida
Tienamicinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Carbapenems); 0 (Cephalosporins); 0 (Penicillin-Binding Proteins); 0 (Thienamycins); 0 (beta-Lactams); BHV525JOBH (doripenem); F52Y83BGH3 (fropenem); FV9J3JU8B1 (meropenem); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:161202
[Lr] Data última revisão:
161202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150408
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.05142-14


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[PMID]:25733506
[Au] Autor:Kocaoglu O; Carlson EE
[Ad] Endereço:Department of Molecular and Cellular Biochemistry, Indiana University Bloomington, Bloomington, Indiana, USA.
[Ti] Título:Profiling of ß-lactam selectivity for penicillin-binding proteins in Escherichia coli strain DC2.
[So] Source:Antimicrob Agents Chemother;59(5):2785-90, 2015 May.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Penicillin-binding proteins (PBPs) are integral players in bacterial cell division, and their catalytic activities can be monitored with ß-lactam-containing chemical probes. Compounds that target a single PBP could provide important information about the specific role(s) of each enzyme, making identification of such molecules important. We evaluated 22 commercially available ß-lactams for inhibition of the PBPs in live Escherichia coli strain DC2. Whole cells were titrated with ß-lactam antibiotics and subsequently incubated with a fluorescent penicillin derivative, Bocillin-FL (Boc-FL), to label uninhibited PBPs. Protein visualization was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separation and fluorescent scanning. The examined ß-lactams exhibited diverse PBP selectivities, with amdinocillin (mecillinam) showing selectivity for PBP2, aztreonam, piperacillin, cefuroxime, cefotaxime, and ceftriaxone for PBP3, and amoxicillin and cephalexin for PBP4. The remaining ß-lactams did not block any PBPs in the DC2 strain of E. coli or inhibited more than one PBP at all examined concentrations in this Gram-negative organism.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Escherichia coli/efeitos dos fármacos
Escherichia coli/metabolismo
Proteínas de Ligação às Penicilinas/metabolismo
beta-Lactamas/farmacologia
[Mh] Termos MeSH secundário: Andinocilina/farmacologia
Aztreonam/farmacologia
Cefotaxima/farmacologia
Cefuroxima/farmacologia
Escherichia coli/genética
Testes de Sensibilidade Microbiana
Proteínas de Ligação às Penicilinas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Penicillin-Binding Proteins); 0 (beta-Lactams); G2B4VE5GH8 (Aztreonam); N2GI8B1GK7 (Cefotaxime); O1R9FJ93ED (Cefuroxime); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150304
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.04552-14


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[PMID]:25583718
[Au] Autor:Thulin E; Sundqvist M; Andersson DI
[Ad] Endereço:Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
[Ti] Título:Amdinocillin (Mecillinam) resistance mutations in clinical isolates and laboratory-selected mutants of Escherichia coli.
[So] Source:Antimicrob Agents Chemother;59(3):1718-27, 2015 Mar.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Amdinocillin (mecillinam) is a ß-lactam antibiotic that is used mainly for the treatment of uncomplicated urinary tract infections. The objectives of this study were to identify mutations that confer amdinocillin resistance on laboratory-isolated mutants and clinical isolates of Escherichia coli and to determine why amdinocillin resistance remains rare clinically even though resistance is easily selected in the laboratory. Under laboratory selection, frequencies of mutation to amdinocillin resistance varied from 8 × 10(-8) to 2 × 10(-5) per cell, depending on the concentration of amdinocillin used during selection. Several genes have been demonstrated to give amdinocillin resistance, but here eight novel genes previously unknown to be involved in amdinocillin resistance were identified. These genes encode functions involved in the respiratory chain, the ribosome, cysteine biosynthesis, tRNA synthesis, and pyrophosphate metabolism. The clinical isolates exhibited significantly greater fitness than the laboratory-isolated mutants and a different mutation spectrum. The cysB gene was mutated (inactivated) in all of the clinical isolates, in contrast to the laboratory-isolated mutants, where mainly other types of more costly mutations were found. Our results suggest that the frequency of mutation to amdinocillin resistance is high because of the large mutational target (at least 38 genes). However, the majority of these resistant mutants have a low growth rate, reducing the probability that they are stably maintained in the bladder. Inactivation of the cysB gene and a resulting loss of cysteine biosynthesis are the major mechanism of amdinocillin resistance in clinical isolates of E. coli.
[Mh] Termos MeSH primário: Andinocilina/farmacologia
Farmacorresistência Bacteriana/genética
Escherichia coli/efeitos dos fármacos
Escherichia coli/genética
Mutação/genética
[Mh] Termos MeSH secundário: Proteínas de Bactérias/genética
Laboratórios
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (CysB protein, Bacteria); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150114
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.04819-14


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[PMID]:25534806
[Au] Autor:Nunes-Alves C
[Ti] Título:Antimicrobials: New tricks for old drugs.
[So] Source:Nat Rev Microbiol;13(2):68, 2015 Feb.
[Is] ISSN:1740-1534
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Andinocilina/farmacologia
Antibacterianos/farmacologia
Escherichia coli/efeitos dos fármacos
beta-Lactamas/farmacologia
[Pt] Tipo de publicação:COMMENT; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (beta-Lactams); V10579P3QZ (Amdinocillin)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141224
[St] Status:MEDLINE
[do] DOI:10.1038/nrmicro3421



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