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FEBS Letters Jan 2016Penicillin-binding protein 3 (PBP3) from Pseudomonas aeruginosa is the molecular target of β-lactam-based antibiotics. Structures of PBP3 in complexes with azlocillin...
Penicillin-binding protein 3 (PBP3) from Pseudomonas aeruginosa is the molecular target of β-lactam-based antibiotics. Structures of PBP3 in complexes with azlocillin and cefoperazone, which are in clinical use for the treatment of pseudomonad infections, have been determined to 2.0 Å resolution. Together with data from other complexes, these structures identify a common set of residues involved in the binding of β-lactams to PBP3. Comparison of wild-type and an active site mutant (S294A) showed that increased thermal stability of PBP3 following azlocillin binding was entirely due to covalent binding to S294, whereas cefoperazone binding produces some increase in stability without the covalent link. Consistent with this, a third crystal structure was determined in which the hydrolysis product of cefoperazone was noncovalently bound in the active site of PBP3. This is the first structure of a complex between a penicillin-binding protein and cephalosporic acid and may be important in the design of new noncovalent PBP3 inhibitors.
Topics: Acylation; Azlocillin; Cefoperazone; Crystallography, X-Ray; Models, Molecular; Molecular Structure; Penicillin-Binding Proteins
PubMed: 26823174
DOI: 10.1002/1873-3468.12054 -
Antimicrobial Agents and Chemotherapy Apr 1980Minimum inhibitory concentrations and agar disk diffusion tests were determined on clinical isolates of beta-lactamase-positive and beta-lactamase-negative Neisseria... (Comparative Study)
Comparative Study
In vitro antimicrobial activity of cefoperazone, cefotaxime, moxalactam (LY127935), azlocillin, mezlocillin, and other beta-lactam antibiotics against Neisseria gonorrhoeae and Haemophilus influenzae, including beta-lactamase-producing strains.
Minimum inhibitory concentrations and agar disk diffusion tests were determined on clinical isolates of beta-lactamase-positive and beta-lactamase-negative Neisseria gonorrhoeae and Haemophilus influenzae with the newer beta-lactam antibiotics, cefoperazone, cefotaxime, moxalactam (LY127935), azlocillin, mezlocillin, and piperacillin, and with seven older beta-lactam antibiotics. All the drugs were active against beta-lactamase-negative strains of N. gonorrhoeae and H. influenzae. The drug most active against beta-lactamase-positive N. gonorrhoeae was cefotaxime, followed closely by cefoperazone, moxalactam, piperacillin, and mezlocillin. The drugs most active against beta-lactamase-positive strains of H. influenzae were cefotaxime, moxalactam, cefoperazone, and cefamandole.
Topics: Azlocillin; Cefoperazone; Cefotaxime; Cephalosporins; Cephamycins; Haemophilus influenzae; Mezlocillin; Microbial Sensitivity Tests; Moxalactam; Neisseria gonorrhoeae; Penicillin Resistance; Penicillins; beta-Lactamases
PubMed: 6249195
DOI: 10.1128/AAC.17.4.757 -
Chemical Biology & Drug Design Jun 2006The need to discover and develop new antimalarial therapeutics is overwhelming. The annual mortality attributed to malaria, currently approximately 2.5 million, is...
The need to discover and develop new antimalarial therapeutics is overwhelming. The annual mortality attributed to malaria, currently approximately 2.5 million, is increasing due primarily to widespread resistance to currently used drugs. One strategy to identify new treatment alternatives for malaria is to examine libraries of diverse compounds for the possible identification of novel scaffolds. Beginning with libraries of drug or drug-like compounds is an ideal starting point because, in the case of approved drugs, substantial pharmacokinetic and toxicologic data should be available for each compound series. We have employed a high-throughput screen of the MicroSource Spectrum and Killer Collections, a library of known drugs, bioactive compounds, and natural products. Our screening assay identifies compounds that inhibit growth of Plasmodium falciparum cultured in human erythrocytes. We have identified 36 novel inhibitors of P. falciparum, of which 19 are therapeutics, and five of these drugs exhibit effective 50% inhibitory concentrations within similar ranges to therapeutic serum concentrations for their recently indicated uses: propafenone, thioridazine, chlorprothixene, perhexiline, and azlocillin. The findings we report here indicate that this is an effective strategy to identify novel scaffolds and therefore aid in antimalarial drug discovery efforts.
Topics: Animals; Antimalarials; Drug Design; Drug Evaluation, Preclinical; Malaria, Falciparum; Molecular Structure; Plasmodium falciparum
PubMed: 16882315
DOI: 10.1111/j.1747-0285.2006.00391.x -
The Journal of Antibiotics Feb 1978The synergistic activities of netilmicin, gentamicin and amikacin combined with carbenicillin, ticarcillin, azlocillin and mezlocillin were investigated against 32... (Comparative Study)
Comparative Study
The synergistic activities of netilmicin, gentamicin and amikacin combined with carbenicillin, ticarcillin, azlocillin and mezlocillin were investigated against 32 Serratia marcescens isolates. Synergy could be demonstrated by killing curve technique, isobologram plots as susceptibility data with any of the aminoglycosides and penicillins combinations. No antagonism was shown with any of the combinations. The majority of the isolates were resistant to the aminoglycosides and penicillins. Combination of either ureido-penicillin or carbenicillin with gentamicin or netilmicin did not reduce the MIC values to levels achievable in serum but did reduce the MIC levels of both agents to those achievable in urine. The combination of ureido-penicillins or carbenicillin and ticarcillin with amikacin reduced the inhibitory levels of all isolates to levels achievable in both serum and urine.
Topics: Amikacin; Carbenicillin; Drug Synergism; Gentamicins; Kanamycin; Microbial Sensitivity Tests; Penicillins; Serratia marcescens; Sisomicin; Ticarcillin; Time Factors
PubMed: 344298
DOI: 10.7164/antibiotics.31.135 -
Biomaterials May 2023Lung bacterial infections could result in acute lung inflammation/injury (ALI) that propagates to its severe form, acute respiratory distress syndrome (ADRS) leading to...
Lung bacterial infections could result in acute lung inflammation/injury (ALI) that propagates to its severe form, acute respiratory distress syndrome (ADRS) leading to the death. The molecular mechanism of ALI is associated with bacterial invasion and the host inflammation response. Here, we proposed a novel strategy to specifically target both bacteria and inflammatory pathways by co-loading of antibiotics (azlocillin, AZ) and anti-inflammatory agents (methylprednisolone sodium, MPS) in neutrophil nanovesicles. We found that cholesterol infilling in the membrane of nanovesicles can maintain a pH gradient between intra-vesicles and outer-vesicles, so we remotely loaded both AZ and MPS in single nanovesicles. The results showed that loading efficiency of both drugs can achieve more than 30% (w/w), and delivery of both drugs using nanovesicles accelerated bacterial clearance and resolved inflammation responses, thus preventing the potential lung damage due to infections. Our studies show that remote loading of multiple drugs in neutrophil nanovesicles which specifically target the infectious lung could be translational to treat ARDS.
Topics: Humans; Neutrophils; Pharmaceutical Preparations; Lung; Pneumonia; Inflammation; Respiratory Distress Syndrome; Bacterial Infections; Bacteria
PubMed: 36878092
DOI: 10.1016/j.biomaterials.2023.122071 -
Antimicrobial Agents and Chemotherapy Jul 1980Azlocillin was relatively ineffective against actively growing cultures of Pseudomonas aeruginosa in tests of bacteriolytic and bactericidal activity in which... (Comparative Study)
Comparative Study
Azlocillin was relatively ineffective against actively growing cultures of Pseudomonas aeruginosa in tests of bacteriolytic and bactericidal activity in which ticarcillin demonstrated pronounced bactericidal effects over a wide range of concentrations. Microscopic observation showed that azlocillin generally induced the formation of filamentous cells of P. aeruginosa which lysed only slowly, but ticarcillin caused the production of spheroplasts and subsequent rapid lysis. During the course of the bactericidal tests, azlocillin was inactivated, presumably by the beta-lactamase produced by P. aeruginosa, and the filamentous cells resumed normal cell division and growth. In contrast, there was no loss of ticarcillin activity, and there was no evidence of resumption of growth of P. aeruginosa in the presence of ticarcillin. These results suggest that the different bactericidal effects demonstrated by azlocillin and ticarcillin against P. aeruginosa are related primarily to dose-related differences in inhibition of cell wall synthesis and secondarily to the instability of azlocillin to pseudomonal beta-lactamase.
Topics: Azlocillin; Bacteriolysis; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Penicillins; Pseudomonas aeruginosa; Ticarcillin; Time Factors
PubMed: 6774663
DOI: 10.1128/AAC.18.1.182 -
Antimicrobial Agents and Chemotherapy May 1977The activity of azlocillin, a new semisynthetic penicillin, was determined against 582 clinical isolates of gram-negative bacilli and gram-positive cocci. Over 75% of... (Comparative Study)
Comparative Study
The activity of azlocillin, a new semisynthetic penicillin, was determined against 582 clinical isolates of gram-negative bacilli and gram-positive cocci. Over 75% of the isolates of Pseudomonas aeruginosa were inhibited at a concentration of 12.5 mug or less per ml. Azlocillin is also active against indole-negative and -positive Proteus spp., inhibiting 98 and 71%, respectively, at a concentration of 12.5 mug or less per ml. Isolates of Klebsiella spp. and Enterobacter spp. showed less susceptibility than isolates of Escherichia coli and Serratia spp. Gram-positive cocci except penicillin G-resistant Staphylococcus aureus were susceptible to azlocillin. Azlocillin failed to inhibit the growth of gram-negative bacilli when large inocula were used. It was more active in alkaline pH, but the type of medium used had little effect on its activity. Azlocillin was more active than mezlocillin, ticarcillin, and carbenicillin and as active as BLP-1654 against isolates of P. aeruginosa. It was not as active as mezlocillin against the majority of the other gram-negative bacilli.
Topics: Bacteria; Enterobacteriaceae; Hydrogen-Ion Concentration; Microbial Sensitivity Tests; Penicillins; Pseudomonas aeruginosa; Staphylococcus aureus; Streptococcus
PubMed: 18083
DOI: 10.1128/AAC.11.5.865 -
Antimicrobial Agents and Chemotherapy Jul 1984The degree of the inoculum effect shown by the new beta-lactam antibiotics with Pseudomonas aeruginosa was investigated, and the antibiotics were divided into three...
The degree of the inoculum effect shown by the new beta-lactam antibiotics with Pseudomonas aeruginosa was investigated, and the antibiotics were divided into three groups based upon the observations. The group 1 antibiotics (cefotaxime, moxalactam, cefoperazone, azlocillin, piperacillin, and aztreonam) demonstrated a large inoculum effect, were poorly bactericidal, produced aberrant, elongated bacilli, and did not inhibit the increase in turbidity of high inocula during an 18-h incubation. The group 2 antibiotics (ceftazidime and ticarcillin) were slowly bactericidal, caused minimal formation of aberrant, elongated bacilli, and slowly decreased the turbidity of high inocula. The group 3 antibiotics (imipenem and gentamicin) were bactericidal, did not cause the formation of elongated bacilli, and decreased the turbidity of high inocula rapidly. Data are presented which suggest that the inoculum effect seen with the group 1 beta-lactam antibiotics is related to (i) the poor intrinsic antibactericidal activity of these antibiotics for P. aeruginosa at the inocula tested and (ii) failure of these antibiotics to inhibit the formation of aberrant and filamentous bacilli, which can result in increased bacterial mass and turbidity.
Topics: Amino Acids; Anti-Bacterial Agents; Drug Resistance, Microbial; Gentamicins; Kinetics; Microbial Sensitivity Tests; Nephelometry and Turbidimetry; Pseudomonas aeruginosa; beta-Lactamases; beta-Lactams
PubMed: 6433787
DOI: 10.1128/AAC.26.1.42 -
Antimicrobial Agents and Chemotherapy Sep 1991This study was undertaken to compare the susceptibility to inactivation of isepamicin with amikacin and gentamicin when exposed to different beta-lactams, beta-lactamase... (Comparative Study)
Comparative Study
This study was undertaken to compare the susceptibility to inactivation of isepamicin with amikacin and gentamicin when exposed to different beta-lactams, beta-lactamase inhibitors, and heparin. The aminoglycosides (5, 10, 20, and 50 micrograms/ml) were incubated in human serum with ampicillin, azlocillin, aztreonam, carbenicillin, ceftazidime, piperacillin, and ticarcillin (100 and 600 micrograms/ml) and with clavulanate, cilastatin, 1:1 imipenemcilastatin, oxacillin, and sulbactam (20 and 120 micrograms/ml) for 48 h at 37 degrees C. Aminoglycoside concentrations were measured by fluorescence polarization immunoassay (FPI) after 0, 8, and 48 h of incubation and by radial diffusion bioassay after 48 h of incubation. Each of the three aminoglycosides was also added to whole blood containing either heparin (100 U/ml) or 0.5% EDTA as a control and assayed after 6 h by FPI. The degree of inactivation of isepamicin by the beta-lactams was significantly less than that by amikacin (P less than 0.003) and gentamicin (P less than 0.0002) when determined by bioassay. Piperacillin, carbenicillin, and azlocillin produced the greatest amount of inactivation, and cilastatin and oxacillin produced the least. A similar pattern was observed when the degree of inactivation was measured by FPI. A significant difference in the degree of inactivation was noted between isepamicin and gentamicin (P less than 0.003 at 8 h and P less than 0.006 at 48 h) but not between isepamicin and amikacin (P greater than 0.7 at 8 h and P greater than 0.08 at 48 h). Aminoglycoside determinations by FPI were not influenced by the presence of heparin. In summary, isepamicin was found to be at least as stable as amikacin against inactivation by beta-lactam compounds and beta-lactamase inhibitors. Heparin (100 U/ml) did not influence aminoglycoside determinations by FPI.
Topics: Amikacin; Anti-Bacterial Agents; Cilastatin; Drug Interactions; Fluorescence Polarization Immunoassay; Gentamicins; Heparin; Humans; beta-Lactamase Inhibitors; beta-Lactams
PubMed: 1952861
DOI: 10.1128/AAC.35.9.1875 -
Applied and Environmental Microbiology Jul 2016This study aimed to isolate nontuberculous mycobacterial species from environmental samples obtained from some selected communities in Ghana. To optimize...
UNLABELLED
This study aimed to isolate nontuberculous mycobacterial species from environmental samples obtained from some selected communities in Ghana. To optimize decontamination, spiked environmental samples were used to evaluate four decontamination solutions and supplemented media, after which the best decontamination solution and media were used for the actual analysis. The isolates obtained were identified on the basis of specific genetic sequences, including heat shock protein 65, IS2404, IS2606, rpoB, and the ketoreductase gene, as needed. Among the methods evaluated, decontamination with 1 M NaOH followed by 5% oxalic acid gave the highest rate of recovery of mycobacteria (50.0%) and the lowest rate of contamination (15.6%). The cultivation medium that supported the highest rate of recovery of mycobacteria was polymyxin B-amphotericin B-nalidixic acid-trimethoprim-azlocillin-supplemented medium (34.4%), followed by isoniazid-supplemented medium (28.1%). Among the 139 samples cultivated in the main analysis, 58 (41.7%) yielded mycobacterial growth, 70 (50.4%) had no growth, and 11 (7.9%) had all inoculated tubes contaminated. A total of 25 different mycobacterial species were identified. Fifteen species (60%) were slowly growing (e.g., Mycobacterium ulcerans, Mycobacterium avium, Mycobacterium mantenii, and Mycobacterium malmoense), and 10 (40%) were rapidly growing (e.g., Mycobacterium chelonae, Mycobacterium fortuitum, and Mycobacterium abscessus). The occurrence of mycobacterial species in the various environmental samples analyzed was as follows: soil, 16 species (43.2%); vegetation, 14 species (38.0%); water, 3 species (8.0%); moss, 2 species (5.4%); snail, 1 species (2.7%); fungi, 1 species (2.7%). This study is the first to report on the isolation of M. ulcerans and other medically relevant nontuberculous mycobacteria from different environmental sources in Ghana.
IMPORTANCE
Diseases caused by mycobacterial species other than those that cause tuberculosis and leprosy are increasing. Control is difficult because the current understanding of how the organisms are spread and where they live in the environment is limited, although this information is needed to design preventive measures. Growing these organisms from the environment is also difficult, because the culture medium becomes overgrown with other bacteria that also live in the environment, such as in soil and water. We aimed to improve the methods for growing these organisms from environmental sources, such as soil and water samples, for better understanding of important mycobacterial ecology.
Topics: Bacterial Proteins; Bacteriological Techniques; Buruli Ulcer; Culture Media; DNA Transposable Elements; Decontamination; Endemic Diseases; Environmental Microbiology; Ghana; Humans; Nontuberculous Mycobacteria; Specimen Handling
PubMed: 27208141
DOI: 10.1128/AEM.01002-16