Disease relevance of Penicillin

• Fragmentation of benzylpenicillin after interaction with the exocellular DD-carboxypeptidase-transpeptidases of Streptomyces R61 and R39 [1].
• Identification of the lethal target of benzylpenicillin in Streptococcus faecalis by in vivo penicillin binding studies [2].
• Landmark article Aug 12, 1944: Penicillin in the treatment of meningitis. By D.H.Rosenberg and P.A.Arling [3].
• Landmark perspective: Penicillin and early syphilis [4].
• Lack of DsbD protein leads to some, but not all, of the phenotypic defects observed with other dsb mutations, such as hypersensitivity to dithiothreitol and to benzylpenicillin [5].

High impact information on Penicillin

• INTERPRETATION: For children with severe pneumonia in less-developed countries the probability of a good outcome is similar if treated with chloramphenicol or with the combination of benzylpenicillin and gentamicin [6].
• Chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in Papua New Guinea: a randomised trial [6].
• INTERPRETATION: We suggest that tuberculosis is a sufficiently common cause of acute pneumonia in Kenyan adults to justify routine sputum culture, and that treatment with benzylpenicillin remains appropriate for clinical failure due to M. tuberculosis, intermediate-resistant pneumococci, and other bacterial pathogens [7].
• This appears to be the first reported case where a point mutation leads to a change in enzyme mechanism resulting in a substantially altered product, effectively changing the product specificity of beta-lactamase into that of D-Ala-D-Ala-carboxypeptidase interacting with benzylpenicillin [8].
• Null mutations in dsbB conferred pleiotropic phenotypes such as sensitivity to benzylpenicillin and inability to support plaque formation of filamentous phages, and they were shown to severely affect disulfide bond oxidation of secreted proteins such as OmpA and beta-lactamase [9].

Chemical compound and disease context of Penicillin

• Structural and Functional Analysis of a Conjugated Bile Salt Hydrolase from Bifidobacterium longum Reveals an Evolutionary Relationship with Penicillin V Acylase [10].
• Malignant otitis externa caused by Pseudomonas aeruginosa, osteomyelitis caused by Staphylococcus aureus, and bacterial endocarditis caused by an enterococcus were treated with carbenicillin, nafcillin, and benzylpenicillin G, respectively [11].
• CONCLUSIONS: Penicillin and azithromycin prophylaxis were found to be effective in decreasing streptococcal infections and neuropsychiatric symptom exacerbations among children in the PANDAS subgroup [12].
• A constant benzylpenicillin (penicillin G) concentration for determination of the MIC for strains of Borrelia burgdorferi was achieved by dialysis culture [13].
• The quantitative relation between granulocytopenia and antibiotic treatment was established for a short-term Staphylococcus aureus infection in the thighs of mice, using rifampin, benzylpenicillin, and erythromycin [14].

Biological context of Penicillin

• At position 105, the small residues alanine and glycine provide weak substrate discrimination as evidenced by the difference in benzylpenicillin hydrolysis relative to cephalothin, two typical penicillin and cephalosporin antibiotics [15].
• Although acylation of the modified proteins by benzylpenicillin remained relatively fast, it was significantly impaired when compared to that observed with the wild-type enzyme [16].
• A beta-lactamase mutant (E166A) binds irreversibly benzylpenicillin via Ser(70) in the active site [17].
• Mechanisms of antibiotic resistance: QM/MM modeling of the acylation reaction of a class A beta-lactamase with benzylpenicillin [18].
• When starting with a rather high cell density, a good beta-lactamase substrate such as benzylpenicillin is too sensitive to beta-lactamase-mediated hydrolysis to allow full induction [19].

Anatomical context of Penicillin

• Functional biosynthesis of cell wall peptidoglycan by polymorphic bifunctional polypeptides. Penicillin-binding protein 1Bs of Escherichia coli with activities of transglycosylase and transpeptidase [20].
• Inhibition of translocation of beta -lactamase into the yeast endoplasmic reticulum by covalently bound benzylpenicillin [17].
• Although the 321-amino acid-long N-terminal fusion partner adopts no regular secondary structure and should have no constraints for pore penetration, the benzylpenicillin-bound protein remained fully exposed to the cytosol, maintaining its signal peptide [17].
• We reported previously that an efficient efflux system for benzylpenicillin (PCG) is located on the choroid plexus (CP) [21].
• In vitro benzylpenicillin preparation contracted the tracheas of the guinea pigs immunized with BPO-As [22].

Associations of Penicillin with other chemical compounds

• 5. The Vmax changed with pH in a bell-shaped curve in the case of benzylpenicillin, but the Vmax for cloxacillin changed only within a small range [23].
• It is characterized by a high beta-lactam-binding activity (second order rate constant for the acylation of the active site serine by benzylpenicillin: k2/K = 300 mm(-1) s(-1)) [24].
• The refolded PBP3** bound benzylpenicillin in a 1 to 1 molar ratio, was highly sensitive to aztreonam and showed the same degree of thermostability, in terms of penicillin-binding capacity, as the parent, membrane-bound PBP3, suggesting that protein refolding occurred with formation of the correct intramolecular interactions [25].
• METHODS: We used skin tests with penicilloylpolylysine, minor determinant mixture, benzylpenicillin, ampicillin, and amoxicillin, as well as patch tests with the last 3 drugs [26].
• Covalent complexes with benzylpenicillin and oxacillin provide evidence that serine acylation does not entail significant structural changes, thus supporting the hypothesis that additional extracellular segments of MecR1 are involved in signal transmission [27].

Gene context of Penicillin

• Exogenous GSH restores defective swarming motility and benzylpenicillin sensitivity in a cydD mutant and also benzylpenicillin sensitivity in a gshA mutant defective in GSH synthesis [28].
• These three strains produced two beta-lactamases with pIs of 5.4 (TEM-1) and 7.6. beta-Lactamase assays revealed that the pI 7.6 enzyme hydrolyzed cefotaxime faster (at a relative hydrolysis rate of 30% compared with that of benzylpenicillin) than either ceftazidime or aztreonam (relative hydrolysis rates of 13 and 3.3%, respectively) [29].
• We have previously shown that the beta-lactam antibiotic benzylpenicillin (BP) conjugates to IFN-gamma and reduces its activity [30].
• For OAT3, there was no species difference in the K(m) values and in the relative transport activities of nine substrates with regard to benzylpenicillin transport between monkey and human [31].
• The benzylpenicillin-bound protein adhered to the endoplasmic reticulum membrane, where it prevented translocation of BiP, carboxypeptidase Y, and secretory proteins [17].

Analytical, diagnostic and therapeutic context of Penicillin

• Molecular cloning and expression in different microbes of the DNA encoding Pseudomonas putida U phenylacetyl-CoA ligase. Use of this gene to improve the rate of benzylpenicillin biosynthesis in Penicillium chrysogenum [32].
• Since neither AmpD nor AmpE are needed for beta-lactam induction and since these proteins could not be covalently labelled by benzylpenicillin, they are not thought to act as beta-lactam-binding sensory transducers [33].
• Two patients had a positive skin test result to penicillin determinants, and 22 patients had a negative result to penicillin determinants and tolerated benzylpenicillin administration [34].
• Penicillin-binding proteins in culture supernatant and cytoplasm and minimum inhibitory concentrations of these strains against benzylpenicillin were also examined [35].
• The bags were sampled at timed intervals and benzylpenicillin concentrations assayed by HPLC [36].

References