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EBioMedicine Apr 2019Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a...
BACKGROUND
Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment.
METHODS
In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions.
FINDINGS
We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line.
INTERPRETATION
Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.
Topics: Cell Line, Tumor; Cell Survival; Drug Discovery; Drug Repositioning; Gene Expression Profiling; Genes, Reporter; Genome, Human; Genomics; Humans; Male; Metabolic Networks and Pathways; Metabolomics; Piperidines; Prostatic Neoplasms; Proteome; Proteomics
PubMed: 30905848
DOI: 10.1016/j.ebiom.2019.03.009 -
Antimicrobial Agents and Chemotherapy Dec 1981The penicillin-binding proteins (PBPs) of Clostridium perfringens were studied. Six PBPs ranging in molecular weight from approximately 42,000 to 100,000 were detected...
The penicillin-binding proteins (PBPs) of Clostridium perfringens were studied. Six PBPs ranging in molecular weight from approximately 42,000 to 100,000 were detected in the cytoplasmic membrane. The relative affinities of the PBPs for 16 beta-lactam antibiotics were determined. Most of the drug saturated PBP 3 and 4 at concentrations equal to their minimal inhibitory concentrations, suggesting that these PBPs are the killing targets for beta-lactams. Mecillinam showed unique properties; it had a higher affinity for PBP 5 than for other PBPs, and it was the only agent tested which caused inhibition of growth without saturating PBP 4. Interestingly, all beta-lactam antibiotics tested induced filament formation despite having different binding patterns to the PBPs of C. perfringens.
Topics: Azlocillin; Bacterial Proteins; Carrier Proteins; Cell Membrane; Clostridium perfringens; Hexosyltransferases; Imidazolidines; Lactams; Muramoylpentapeptide Carboxypeptidase; Penicillin-Binding Proteins; Penicillins; Peptidyl Transferases
PubMed: 6275787
DOI: 10.1128/AAC.20.6.809 -
Clinical Pharmacokinetics Nov 2021Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex...
BACKGROUND
Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data.
OBJECTIVE
The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates.
METHODS
Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods.
RESULTS
The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods.
CONCLUSION
A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data.
Topics: Drug Elimination Routes; Humans; Infant, Newborn; Machine Learning; Metabolic Clearance Rate; Models, Biological; Vancomycin
PubMed: 34041714
DOI: 10.1007/s40262-021-01033-x -
Antimicrobial Agents and Chemotherapy Jul 1982The standardized disk diffusion test was performed with 75-micrograms azlocillin disks to determine individual test, accuracy, and precision control values with...
The standardized disk diffusion test was performed with 75-micrograms azlocillin disks to determine individual test, accuracy, and precision control values with Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 25923. In addition, regression lines for correlating inhibitory zone diameters with the 75-micrograms azlocillin disk and azlocillin minimal inhibitory concentrations were calculated for gram-negative clinical isolates (including Enterobacteriaceae, P. Aeruginosa, other nonfermenters, and Aeromonas hydrophila). Criteria for distinguishing susceptible isolates from resistant isolates, based on an error-rate bound classification scheme, are proposed.
Topics: Azlocillin; Bacteria; Microbial Sensitivity Tests; Penicillins; Quality Control
PubMed: 7125631
DOI: 10.1128/AAC.22.1.28 -
The Journal of Pediatrics Apr 1999We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
UNLABELLED
We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis.
STUDY DESIGN
Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization.
RESULTS
No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy.
CONCLUSION
We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.
Topics: Adolescent; Analysis of Variance; Anti-Bacterial Agents; Azlocillin; Child; Cystic Fibrosis; DNA, Bacterial; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Male; Penicillins; Pseudomonas aeruginosa; Respiratory Function Tests; Sputum; Tobramycin; Vital Capacity
PubMed: 10190914
DOI: 10.1016/s0022-3476(99)70197-6 -
Applied and Environmental Microbiology Jun 2010The environment is the likely source of most nontuberculous mycobacteria (NTM) involved in human infections, especially pulmonary, skin, and soft tissue infections. In...
The environment is the likely source of most nontuberculous mycobacteria (NTM) involved in human infections, especially pulmonary, skin, and soft tissue infections. In order to measure the prevalence of NTM in different aquatic ecosystems, we tried to standardize the culture methods used for surface water testing since many procedures have been described previously. Cultivation of mycobacteria requires long-term incubation in rich media and inactivation of rapidly growing microorganisms whose growth impedes observation of mycobacterial colonies. Consequently, the two criteria used for evaluation of the methods examined were (i) the rate of inhibition of nontarget microorganisms and (ii) the efficiency of recovery of mycobacteria. We compared the competitive growth of Mycobacterium chelonae and M. avium with nontarget microorganisms on rich Middlebrook 7H11-mycobactin medium after treatment by several chemical decontamination methods that included acids, bases, detergent, or cetylpyridinium chloride (CPC) with and without an antibiotic cocktail, either PANTA (40 U/ml polymyxin, 4 microg/ml amphotericin B, 16 microg/ml nalidixic acid, 4 microg/ml trimethoprim, and 4 microg/ml azlocillin) or PANTAV (PANTA plus 10 microg/ml vancomycin). Our results showed that treatment for 30 min with CPC (final concentration, 0.05%) of water concentrated by centrifugation, followed by culture on a rich medium supplemented with PANTA, significantly decreased the growth of nontarget microorganisms (the concentrations were 6.2 +/- 0.4 log(10) CFU/liter on Middlebrook 7H11j medium and 4.2 +/- 0.2 log(10) CFU/liter on Middlebrook 7H11j medium containing PANTA [P < 0.001]), while the effect of this procedure on NTM was not as great (the concentrations of M. chelonae on the two media were 7.0 +/- 0.0 log(10) CFU/liter and 6.9 +/- 0.0 log(10) CFU/liter, respectively, and the concentrations of M. avium were 9.1 +/- 0.0 log(10) CFU/liter and 8.9 +/- 0.0 log(10) CFU/liter, respectively). We propose that this standardized culture procedure could be used for detection of NTM in aquatic samples.
Topics: Bacteriological Techniques; Culture Media; DNA, Bacterial; DNA, Ribosomal; Molecular Sequence Data; Mycobacterium chelonae; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Water Microbiology
PubMed: 20363776
DOI: 10.1128/AEM.02659-09 -
Antimicrobial Agents and Chemotherapy Oct 1983Uric acid levels in serum were observed to fall precipitously in a group of 20 hospitalized asthmatic patients receiving azlocillin, bronchodilators, and steroids. None... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Uric acid levels in serum were observed to fall precipitously in a group of 20 hospitalized asthmatic patients receiving azlocillin, bronchodilators, and steroids. None of the 20 hospitalized controls receiving the antiasthma therapy without azlocillin showed any decline in their uric acid levels. The levels for the azlocillin-treated group fell from a mean of 6.4 mg/dl to mean of 2.3 mg/dl, whereas those for the control group initially were 7.0 mg/dl and fell only to a mean of 6.5 mg/dl.
Topics: Adolescent; Adult; Aged; Asthma; Azlocillin; Bronchodilator Agents; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Penicillins; Steroids; Uric Acid
PubMed: 6651284
DOI: 10.1128/AAC.24.4.609 -
Antimicrobial Agents and Chemotherapy Jun 1982We assessed the extent and mechanisms of antagonism of beta-lactam antibiotics by cefoxitin. In tests with 41 gram-negative isolates, cefoxitin antagonized cephalothin,...
We assessed the extent and mechanisms of antagonism of beta-lactam antibiotics by cefoxitin. In tests with 41 gram-negative isolates, cefoxitin antagonized cephalothin, cefamandole, cefsulodin, cefotaxime, moxalactam, ampicillin, carbenicillin, piperacillin, mezlocillin, and azlocillin, but not cephalexin, mecillinam, or N-formimidoyl thienamycin. The extent of antagonism varied with the beta-lactam and genus studied. However, antagonism occurred most often with strains possessing inducible cephalosporinases. Antagonism of cephalothin and cefamandole correlated closely with the induction of beta-lactamases capable of inactivating these drugs. Although antagonism of the remaining drugs occurred more often with strains possessing inducible beta-lactamases, these enzymes did not inactivate the drugs. Morphological studies revealed that cefoxitin inhibited filamentation and lysis produced by various beta-lactam drugs. Results of this investigation suggest that cefoxitin antagonizes beta-lactams via (i) induction of drug-inactivating beta-lactamases, and (ii) the induction of beta-lactamases that cannot inactivate the drug but serve as barriers against access to target proteins. This barrier appears most efficient for drugs that bind to penicillin-binding proteins 1 and 3.
Topics: Anti-Bacterial Agents; Bacteria; Cefoxitin; Microbial Sensitivity Tests; beta-Lactamases; beta-Lactams
PubMed: 6981376
DOI: 10.1128/AAC.21.6.968 -
Antimicrobial Agents and Chemotherapy Aug 1979The in vitro activities of the new ureidopenicillins piperacillin, mezlocillin, azlocillin, and Bay k 4999 were compared with those of ampicillin and ticarcillin against... (Comparative Study)
Comparative Study
The in vitro activities of the new ureidopenicillins piperacillin, mezlocillin, azlocillin, and Bay k 4999 were compared with those of ampicillin and ticarcillin against 336 Enterobacteriaceae, 109 nonfermenters, 55 Neisseria, and 28 Haemophilus influenzae isolates. Bay k 4999 displayed the largest spectrum of activity and had lower minimal inhibitory concentrations than any of the other penicillins against all of the species tested. Piperacillin showed the same spectrum but was slightly less active than Bay k 4999; it was slightly more effective than mezlocillin against Enterobacteriaceae and fully as active as azlocillin against Pseudomonas. All ureidopenicillins were substantially more active than ampicillin and ticarcillin. Isolates highly resistant to ampicillin or ticarcillin were also less susceptible to the ureidopenicillins.
Topics: Ampicillin; Azlocillin; Gram-Negative Aerobic Bacteria; Imidazolidines; Microbial Sensitivity Tests; Penicillins; Ticarcillin
PubMed: 485123
DOI: 10.1128/AAC.16.2.115 -
Antimicrobial Agents and Chemotherapy Jun 1998New antibiotic regimens are needed for the treatment of multidrug-resistant tuberculosis. Mycobacterium tuberculosis has a thick peptidoglycan layer, and the...
New antibiotic regimens are needed for the treatment of multidrug-resistant tuberculosis. Mycobacterium tuberculosis has a thick peptidoglycan layer, and the penicillin-binding proteins involved in its biosynthesis are inhibited by clinically relevant concentrations of beta-lactam antibiotics. beta-Lactamase production appears to be the major mechanism by which M. tuberculosis expresses beta-lactam resistance. beta-Lactamases from the broth supernatant of 3- to 4-week-old cultures of M. tuberculosis H37Ra were partially purified by sequential gel filtration chromatography and chromatofocusing. Three peaks of beta-lactamase activity with pI values of 5.1, 4.9, and 4.5, respectively, and which accounted for 10, 78, and 12% of the total postchromatofocusing beta-lactamase activity, respectively, were identified. The beta-lactamases with pI values of 5.1 and 4.9 were kinetically indistinguishable and exhibited predominant penicillinase activity. In contrast, the beta-lactamase with a pI value of 4.5 showed relatively greater cephalosporinase activity. An open reading frame in cosmid Y49 of the DNA library of M. tuberculosis H37Rv with homology to known class A beta-lactamases was amplified from chromosomal DNA of M. tuberculosis H37Ra by PCR and was overexpressed in Escherichia coli. The recombinant enzyme was kinetically similar to the pI 5.1 and 4.9 enzymes purified directly from M. tuberculosis. It exhibited predominant penicillinase activity and was especially active against azlocillin. It was inhibited by clavulanic acid and m-aminophenylboronic acid but not by EDTA. We conclude that the major beta-lactamase of M. tuberculosis is a class A beta-lactamase with predominant penicillinase activity. A second, minor beta-lactamase with relatively greater cephalosporinase activity is also present.
Topics: Drug Resistance, Multiple; Escherichia coli; Isoelectric Focusing; Mycobacterium tuberculosis; Protein Denaturation; Recombinant Proteins; beta-Lactam Resistance; beta-Lactamases
PubMed: 9624479
DOI: 10.1128/AAC.42.6.1375