Abstract:
:Deciphering the mode of action (MOA) of new antibiotics discovered through phenotypic screening is of increasing importance. Metabolomics offers a potentially rapid and cost-effective means of identifying modes of action of drugs whose effects are mediated through changes in metabolism. Metabolomics techniques also collect data on off-target effects and drug modifications. Here, we present data from an untargeted liquid chromatography-mass spectrometry approach to identify the modes of action of eight compounds: 1-[3-fluoro-4-(5-methyl-2,4-dioxo-pyrimidin-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea (AZ1), 2-(cyclobutylmethoxy)-5'-deoxyadenosine, triclosan, fosmidomycin, CHIR-090, carbonyl cyanidem-chlorophenylhydrazone (CCCP), 5-chloro-2-(methylsulfonyl)-N-(1,3-thiazol-2-yl)-4-pyrimidinecarboxamide (AZ7), and ceftazidime. Data analysts were blind to the compound identities but managed to identify the target as thymidylate kinase for AZ1, isoprenoid biosynthesis for fosmidomycin, acyl-transferase for CHIR-090, and DNA metabolism for 2-(cyclobutylmethoxy)-5'-deoxyadenosine. Changes to cell wall metabolites were seen in ceftazidime treatments, although other changes, presumably relating to off-target effects, dominated spectral outputs in the untargeted approach. Drugs which do not work through metabolic pathways, such as the proton carrier CCCP, have no discernible impact on the metabolome. The untargeted metabolomics approach also revealed modifications to two compounds, namely, fosmidomycin and AZ7. An untreated control was also analyzed, and changes to the metabolome were seen over 4 h, highlighting the necessity for careful controls in these types of studies. Metabolomics is a useful tool in the analysis of drug modes of action and can complement other technologies already in use.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Vincent IM,Ehmann DE,Mills SD,Perros M,Barrett MPdoi
10.1128/AAC.02109-15subject
Has Abstractpub_date
2016-03-25 00:00:00pages
2281-91issue
4eissn
0066-4804issn
1098-6596pii
AAC.02109-15journal_volume
60pub_type
杂志文章abstract::Parallel administration of the proton pump inhibitor (PPI) esomeprazole has been shown to decrease oral bioavailability of posaconazole in healthy volunteers. We prospectively analyzed serum samples (n = 59) obtained from hematology patients (n = 27) under posaconazole prophylaxis. Patients treated concomitantly with ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00150-10
更新日期:2010-09-01 00:00:00
abstract::The dynamic interaction of planktonic and biofilm cells of mucoid Pseudomonas aeruginosa with tobramycin and piperacillin was investigated in a chemostat system. The results indicated that planktonic and young biofilm cells of the 2-day-old chemostat culture of P. aeruginosa were susceptible to killing by chemostat-co...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.6.1208
更新日期:1992-06-01 00:00:00
abstract::The in vitro susceptibility of Brucella melitensis was examined vis-a-vis the clinical outcome in 75 patients with brucellosis. The initial MICs for Brucella isolates from patients who relapsed and from those who did not were similar. Furthermore, the MICs for isolates from patients whose infections relapsed were no d...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.30.6.958
更新日期:1986-12-01 00:00:00
abstract::The aim of this study was to determine the penetration of doripenem administered intravenously into the rabbit aqueous and vitreous humors. Nineteen New Zealand White rabbits received a 20-mg dose of doripenem intravenously over 60 min. Specimens of aqueous humor, vitreous humor, and blood were obtained 30 min (n = 5)...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.06329-11
更新日期:2012-07-01 00:00:00
abstract::The in vitro sensitivity of Plasmodium falciparum to atorvastatin and rosuvastatin was assessed using chloroquine-sensitive and chloroquine-resistant strains. Although atorvastatin was more potent, it had weak activity (mean 50% inhibitory concentration of > or = 17 microM) and an indifferent interaction with chloroqu...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01469-08
更新日期:2009-05-01 00:00:00
abstract::The dependence of microbial killing on chloride ions present in solutions undergoing iontophoresis is addressed. A 400-microA current was applied to vials containing synthetic urine or saline, and the production of chlorine-based substances (CBSs) was detected by the N,N-diethyl-p-phenylene diamine colorimetric method...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.38.12.2768
更新日期:1994-12-01 00:00:00
abstract::Azoles are widely used antifungals; however, their efficacy is compromised by fungistatic activity and selection of resistant strains during treatment. Recent studies demonstrated roles for the protein kinase C and calcium signaling pathways in modulating azole activity. Here we explored a role for the signaling pathw...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.47.10.3195-3201.2003
更新日期:2003-10-01 00:00:00
abstract::The in vitro effects of 19 dicationic diamidine derivatives against the proliferative tachyzoite stages of the apicomplexan parasites Neospora caninum and Toxoplasma gondii were investigated. Four compounds (DB811, DB786, DB750, and DB766) with similar structural properties exhibited profound inhibition of tachyzoite ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01236-07
更新日期:2008-06-01 00:00:00
abstract::Debio-025 is a synthetic cyclosporine with no immunosuppressive capacity but a high inhibitory potency against cyclophilin A (CypA)-associated cis-trans prolyl isomerase (PPIase) activity. A lack of immunosuppressive effects compared to that of cyclosporine was demonstrated both in vitro and in vivo. For three cyclosp...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01324-07
更新日期:2008-04-01 00:00:00
abstract::Moderately penicillin-resistant Neisseria meningitidis was responsible for an outbreak of meningococcal disease in Saskatoon, Saskatchewan, Canada in 1993. We tested fully susceptible and moderately resistant strains of N. meningitidis against ciprofloxacin, cefotaxime, ceftriaxone, chloramphenicol, penicillin, and ri...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.11.2577
更新日期:1995-11-01 00:00:00
abstract::Selection of resistance to cefamandole has been observed, and the drug has failed to protect animals lethally infected with certain Enterobacteriaceae that appeared to be highly susceptible in vitro. Using spectrophotometric assays, some of these organisms were found to produce beta-lactamases highly active against ce...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.15.6.792
更新日期:1979-06-01 00:00:00
abstract::Ampicillin resistance in Enterococcus faecium is a serious concern worldwide, complicating the treatment of E. faecium infections. Penicillin-binding protein 5 (PBP5) is considered the main ampicillin resistance determinant in E. faecium The three known E. faecium clades showed sequence variations in the pbp5 gene tha...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02034-16
更新日期:2016-12-27 00:00:00
abstract::We tested 32 Candida isolates recovered in the early 1990s from the bloodstreams of patients with candidemia for in vitro susceptibility to fluconazole and determined if MIC and/or the daily dose of fluconazole/MIC ratio correlated with the response to therapy. This is a unique data set since 87.5% (28/32) of patients...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1128/AAC.49.8.3171-3177.2005
更新日期:2005-08-01 00:00:00
abstract::This study summarizes the linezolid susceptibility testing results for 7,429 Gram-positive pathogens from 60 U.S. sites collected during the 2012 sampling year for the LEADER Program. Linezolid showed potent activity when tested against 2,980 Staphylococcus aureus isolates, inhibiting all but 3 at ≤2 μg/ml. Similarly,...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,多中心研究
doi:10.1128/AAC.02112-13
更新日期:2014-01-01 00:00:00
abstract::The role of extracellular DNA in the maintenance of biofilms formed by gram-positive and gram-negative bacteria was studied. This study evaluated all the bacterial strains that were tested for the presence of extracellular DNA with an average size of 30 kb in the matrix. Our results indicate changes in community bioma...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00471-08
更新日期:2009-03-01 00:00:00
abstract::The efficacy of a loading dose of 20 mg of chloroquine per kg of body weight per os given at intervals during the first day was evaluated in 27 patients in Madagascar with Plasmodium falciparum malaria. The conventional regimen of 25 mg/kg over 3 days (schedule 1) was thus compared with a regimen of 30 mg/kg over 2 da...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/aac.35.3.406
更新日期:1991-03-01 00:00:00
abstract::A series of 11 fluoroquinolone antibacterial agents, including 8 newly synthesized molecules and 3 reference compounds (pefloxacin, ciprofloxacin, and sparfloxacin), were tested for their MICs against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The intracellular accumulation of fluoroquinolone...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.12.2622
更新日期:1992-12-01 00:00:00
abstract::Primaquine is currently the only drug available for radical cure of Plasmodium vivax and P. ovale liver infection stages, but limited safety data exist for children <10 years of age. Detailed daily assessments of side effects in glucose-6-phosphate dehydrogenase (G6PD)-normal children treated with 14 days of primaquin...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.05566-11
更新日期:2012-04-01 00:00:00
abstract::The antiviral activity of zinc salts against rhinovirus types 1A and 39 was assayed by yield reduction and inhibition of cytopathic effect in cell culture. The findings indicate that the zinc salts tested have low in vitro therapeutic indices and suggest that the possible beneficial effects of zinc lozenges in reducin...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.31.4.622
更新日期:1987-04-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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abstract::Foscarnet (phosphonoformic acid) is a pyrophosphate analog that inhibits the replication of human immunodeficiency virus type 1 (HIV-1) in vitro and in patients with AIDS. HIV-1 resistance to foscarnet has not been reported despite long-term foscarnet therapy of AIDS patients with cytomegalovirus disease. We therefore...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.5.1087
更新日期:1995-05-01 00:00:00
abstract::PER-2 was the first detected and the second most prevalent extended-spectrum beta-lactamase in clinical pathogens isolated in Argentina and was also reported only in other South American countries. Citrobacter freundii 33587 was isolated in 1999 in Buenos Aires and was resistant to all tested beta-lactams except cepha...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01395-06
更新日期:2007-07-01 00:00:00
abstract::Enfuvirtide is the first fusion and entry inhibitor approved for use for the treatment of human immunodeficiency virus (HIV) type 1 infection and as such represents a novel class of agents. For the population of patients experienced with three antiretroviral classes, enfuvirtide provides an additional option for treat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/AAC.00467-08
更新日期:2008-12-01 00:00:00
abstract::Enzymes in the ergosterol-biosynthetic pathway are the targets of a number of antifungal agents including azoles, allylamines, and morpholines. In order to understand the response of Saccharomyces cerevisiae to perturbations in the ergosterol pathway, genome-wide transcript profiles following exposure to a number of a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.5.1255-1265.2000
更新日期:2000-05-01 00:00:00
abstract::The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treate...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00753-16
更新日期:2016-07-22 00:00:00
abstract::Topical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.05461-11
更新日期:2012-01-01 00:00:00
abstract::beta-Lactamases produced by urine isolates from patients in long-term care facilities (LTCFs), outpatient, clinics, and one hospital in a U.S. community were characterized. A total of 1.3% of all Escherichia coli and Klebsiella pneumoniae isolates collected from patients in 30 LTCFs and various outpatient clinics prod...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00877-08
更新日期:2008-10-01 00:00:00
abstract::A comparison was made of the in vitro activity of ciprofloxacin (Bay o 9867) with nine other antibiotics against isolates of Campylobacter jejuni, Salmonella spp., Shigella spp., Yersinia enterocolitica, Clostridium difficile, Vibrio spp., and Escherichia coli. Minimum inhibitory concentrations of ciprofloxacin were t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.25.4.504
更新日期:1984-04-01 00:00:00
abstract::We determined the pharmacodynamic parameter and the magnitude of that parameter that was predictive of the efficacy of fluconazole in the treatment of disseminated candidiasis. We used a neutropenic murine model of disseminated Candida albicans infection to characterize the time course of activity of fluconazole. Quan...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.9.2116
更新日期:1999-09-01 00:00:00
abstract::The effect of liposomal encapsulation of ampicillin on the antibacterial activity against intracellular Listeria monocytogenes was studied by comparing survival of L. monocytogenes within peritoneal mouse macrophages in the presence of free ampicillin alone or in combination with liposome-entrapped ampicillin. In the ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.30.2.295
更新日期:1986-08-01 00:00:00