Rashes with Ampicillin

1980 ◽  
Vol 1 (7) ◽  
pp. 197-201
Author(s):  
Michael J. Kraemer ◽  
Arnold L. Smith
Keyword(s):  
Penicillin G ◽  
Side Chain ◽  
Gram Negative Bacteria ◽  
Acid Moiety ◽  
Structure Activity ◽  
Body Tissues ◽  
The Family ◽  
Acyl Side Chain ◽  
Penicillanic Acid ◽  
Lactam Ring

Ampicillin, first introduced in 1961, has probably become the most widely used penicillin in clinical pediatrics. STRUCTURE ACTIVITY RELATIONSHIPS All penicillins contain the 6-amino penicillanic acid moiety (Fig 1). Its structure includes a thiazolidine ring (A), a β-lactam ring (B), the source of antibacterial activity, and an acyl side chain (R), containing a variety of substitutions creating the family of semisynthetic penicillins. The only difference between ampicillin and penicillin G is the presence of an amino group in the acyl side chain (Fig 1). PHARMACOLOGY AND BACTERIOLOGY Ampicillin is a semisynthetic penicillin, active against Streptococus pneumoniae and certain Gram-negative bacteria, including most Haemophilus influenzae, Escherichia coli, and certain Proteus species. Compared to penicillin G, it has increased stability in acid solutions: a property facilitating oral administration and absorption. It penetrates into most body tissues; effective entry into CSF, however, occurs only with inflamed meninges. The serum half-life with normal renal function varies from four hours in newborns1 to 1.3 hours in adults.2 Ampicillin can cause an allergic, or nonallergic skin rash (Fig 2). ALLERGY Allergy (for the purposes of this discussion) is defined as a specific immunologic interaction, between either antigen and antibody, or antigen with a sensitized lymphocyte, resulting in a clinically deleterious effect. Implicit is a prior contact with the antigen.

scholarly journals Novel Cephalosporin Conjugates Display Potent and Selective Inhibition of IMP Type Metallo-β-Lactamases

2020 ◽  
Author(s):  
Kamaleddin Tehrani ◽  
Nicola Wade ◽  
Vida Mashayekhi ◽  
Nora Brüchle ◽  
Willem Jespers ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Acid Moiety ◽  
Inhibitory Potency ◽  
Structure Activity ◽  
Potent Inhibition ◽  
Lactam Ring ◽  
Acid Conjugate ◽  
Hydrolysis Of ◽  
Nanomolar Range ◽  
Hydrolytic Mechanism

In an attempt to exploit the hydrolytic mechanism by which β-lactamase enzymes degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-β-lactamases (MBLs) in spatiotemporally controlled fashion. Notably, while enzyme-mediated hydrolysis of the β-lactam ring was found to occur, it was not accompanied by release of the thiol-based inhibitors. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (<b>8</b>), demonstrated potent inhibition of IMP-type MBLs, with IC<sub>50</sub> values in the nanomolar range. In addition, conjugate <b>8</b> was also found to greatly reduce the MIC of meropenem against an IMP-28 producing clinical isolate of <i>K. pneumoniae</i>. The results of kinetic experiments indicate that these prodrugs inhibit IMP-type MBLs by acting as slowly turned-over substrates. Structure-activity relationship studies revealed that both phenyl and carboxyl moieties of <b>8</b> are crucial for its potency. Furthermore, modeling studies indicate that productive interactions of the thiomandelic acid moiety of <b>8</b> with residues Trp28 and Lys161 within the IMP active site may contribute to the observed inhibitory potency and selectivity.

Penicillin Update

1995 ◽  
Vol 16 (3) ◽  
pp. 83-90
Author(s):  
Stuart L. Goldstein ◽  
Sheldon L. Kaplan ◽  
Ralph D. Feigin
Keyword(s):  
Cell Wall ◽  
Mechanism Of Action ◽  
Antimicrobial Agents ◽  
Specific Activity ◽  
Basic Structure ◽  
Penicillin G ◽  
Side Chain ◽  
Beta Lactam ◽  
Lactam Ring ◽  
The Stability

Penicillin was discovered serendipitously by Alexander Fleming in 1928 while he was examining Staphylococcus variants. The first trials of penicillin in humans who had serious staphylococcal infections were undertaken more than I decade later and yielded impressive therapeutic results. Despite the introduction of numerous other antimicrobial agents and the emergence of many organisms resistant to penicillin, this agent remains a powerful and essential antibiotic 50 years after its first clinical application. Pharmacology The basic structure of the penicillins consists of the thiazolidine ring, a beta-lactam ring, and a side chain (Figure 1). The antimicrobial activity of all penicillins is produced by the thiazolidine/beta-lactam nucleus, and the organism-specific activity of a particular penicillin is determined by the side chain derivative. There are many naturally occurring side chain derivatives, but penicillin G is the most potent of these and, therefore, the only one used clinically. Semisynthetic penicillins are constructed from the basic penicillin nucleus with a side chain added. Each side chain alters the susceptibility of a particular penicillin to inactivating enzymes. MECHANISM OF ACTION All pencillins work by inhibiting bacterial cell wall synthesis, thereby affecting the stability of the cell wall and subsequent bacterial development. The cell wall is made of a peptidoglycan that is synthesized in three stages. MECHANISM OF ACTION

Examination of various Gram-negative bacteria for beta-lactamase activity

1968 ◽  
Vol 14 (5) ◽  
pp. 601-603 ◽  
Author(s):  
Pragna Desai ◽  
M. Goldner
Keyword(s):  
Quantitative Data ◽  
Direct Evidence ◽  
Bacterial Species ◽  
Penicillin G ◽  
Gram Negative Bacteria ◽  
Beta Lactamase ◽  
Infrared Spectrophotometry ◽  
Beta Lactam ◽  
Lactam Ring

The beta-lactamase activity in 10 bacterial species from different genera were evaluated where direct evidence and quantitative data were lacking. A quantitative iodometric method and infrared spectrophotometry were used for the determination of the beta-lactamase activity. The organisms tested were shown to have enzyme activity directed against the beta-lactam ring, and on the basis of the activity on two members of the beta-lactam group of antibiotics, penicillin G and cephalosporin C, a particular ratio was obtained for each species. This report supports the fact of the widespread distribution of beta-lactamase and reopens the question of its significance.

scholarly journals The pH-dependence and group modification of β-lactamase I

1975 ◽  
Vol 149 (3) ◽  
pp. 547-551 ◽  
Author(s):  
S G Waley
Keyword(s):  
Ph Dependence ◽  
Water Soluble ◽  
Side Chain ◽  
Polar Group ◽  
Woodward’S Reagent K ◽  
Group Modification ◽  
Penicillanic Acid ◽  
Lactam Ring ◽  
Parameter Versus ◽  
Hydrolysis Of

The pH-dependence of the kinetic parameters for the hydrolysis of the β-lactam ring by β-lactamase I (penicillinase, EC 3.5.2.6) was studied. Benzylpenicillin and ampicillin (6-[D(-)-α-aminophenylacetamido]penicillanic acid) were used. Both kcat. and kcat./Km for both substrates gave bell-shaped plots of parameter versus pH. The pH-dependence of kcat./Km for the two substrates gave the same value (8.6) for the higher apparent pK, and so this value may characterize a group on the free enzyme; the lower apparent pK values were about 5(4.85 for benzylpenicillin, 5.4 for ampicillin). For benzylpenicillin both kcat. and kcat./Km depended on pH in exactly the same way. The value of Km for benzylpenicillin was thus independent of pH, suggesting that ionization of the enzyme's catalytically important groups does not affect binding of this substrate. The pH-dependence of kcat. for ampicillin differed, however, presumably because of the polar group in the side chain. The hypothesis that the pK5 group is a carboxyl group was tested. Three reagents that normally react preferentially with carboxyl groups inactivated the enzyme: the reagents were Woodward's reagent K, a water-soluble carbodi-imide, and triethyloxonium fluoroborate. These findings tend to support the idea that a carboxylate group plays a part in the action of β-lactamase I.

scholarly journals Novel Cephalosporin Conjugates Display Potent and Selective Inhibition of IMP Type Metallo-β-Lactamases

2020 ◽  
Author(s):  
Kamaleddin Tehrani ◽  
Nicola Wade ◽  
Vida Mashayekhi ◽  
Nora Brüchle ◽  
Willem Jespers ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Acid Moiety ◽  
Inhibitory Potency ◽  
Structure Activity ◽  
Potent Inhibition ◽  
Lactam Ring ◽  
Acid Conjugate ◽  
Hydrolysis Of ◽  
Nanomolar Range ◽  
Hydrolytic Mechanism

In an attempt to exploit the hydrolytic mechanism by which β-lactamase enzymes degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-β-lactamases (MBLs) in spatiotemporally controlled fashion. Notably, while enzyme-mediated hydrolysis of the β-lactam ring was found to occur, it was not accompanied by release of the thiol-based inhibitors. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (<b>8</b>), demonstrated potent inhibition of IMP-type MBLs, with IC<sub>50</sub> values in the nanomolar range. In addition, conjugate <b>8</b> was also found to greatly reduce the MIC of meropenem against an IMP-28 producing clinical isolate of <i>K. pneumoniae</i>. The results of kinetic experiments indicate that these prodrugs inhibit IMP-type MBLs by acting as slowly turned-over substrates. Structure-activity relationship studies revealed that both phenyl and carboxyl moieties of <b>8</b> are crucial for its potency. Furthermore, modeling studies indicate that productive interactions of the thiomandelic acid moiety of <b>8</b> with residues Trp28 and Lys161 within the IMP active site may contribute to the observed inhibitory potency and selectivity.

scholarly journals Des-, syn- and anti-oxyimino-Δ3-cephalosporins. Intrinsic reactivity and reaction with RTEM-2 serine β-lactamase and d-alanyl-d-alanine-cleaving serine and Zn2+-containing peptidases

1984 ◽  
Vol 218 (3) ◽  
pp. 933-937 ◽  
Author(s):  
G Laurent ◽  
F Durant ◽  
J M Frere ◽  
D Klein ◽  
J M Ghuysen
Keyword(s):  
Side Chain ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Sulphur Atom ◽  
Compound I ◽  
Anti Isomer ◽  
Specific Effects ◽  
Acyl Side Chain ◽  
Lactam Ring ◽  
Intrinsic Reactivity

The presence and configuration (syn or anti) of an oxyimino group in the 7 (beta)-acyl side chain of 3-cephems do not modify the intrinsic reactivity of the beta-lactam ring, but have highly enzyme-specific effects. When compared with the corresponding desoxyimino beta-lactam compound: (i) with the plasmid-mediated Escherichia coli RTEM-2 serine beta-lactamase, the substrate activity of the anti isomer is increased and that of the syn isomer is decreased; (ii) with the Streptomyces R61 serine D-alanyl-D-alanine cleaving peptidase (a highly penicillin-sensitive enzyme), the rate of enzyme acylation is not or only little affected when the oxyimino group is in the syn configuration, but is decreased when the oxyimino group is in the anti configuration; (iii) with the Actinomadura R39 serine D-alanyl-D-alanine-cleaving peptidase (an exceedingly highly penicillin-sensitive enzyme), the rate of enzyme acylation is unaffected whatever the configuration of the substituent. The oxidation of the sulphur atom of the dihydrothiazine ring on the beta-face of the molecule makes it both a poorer inactivator of the DD-peptidases and a poorer substrate of the beta-lactamase. The Streptomyces albus G Zn2+-containing D-alanyl-D-alanine-cleaving peptidase (a highly penicillin-resistant enzyme) remains highly resistant to all compounds tested.

Structure-Activity Relationship and Antimicrobial Evaluation of N-Phenylpyrazole Curcumin Derivatives

2020 ◽  
Vol 16 (4) ◽  
pp. 481-488
Author(s):  
Heli Sanghvi ◽  
Satyendra Mishra
Keyword(s):  
Antibacterial Activity ◽  
Gram Negative Bacteria ◽  
Pyrazole Derivatives ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
Curcumin Derivatives ◽  
Structure Activity ◽  
Electron Donating Groups ◽  
Derivatives Of

Background: Curcumin, one of the most important pharmacologically significant natural products, has gained significant consideration among scientists for decades since its multipharmacological activities. 1, 3-Dicarbonyl moiety of curcumin was found to be accountable for the rapid degradation of curcumin molecule. The aim of present work is to replace 1, 3-dicarbonyl moiety of curcumin by pyrazole and phenylpyrazole derivatives with a view to improving its stability and to investigate the role of substitution in N-phenylpyrazole curcumin on its antibacterial activity against both Gram-positive as well as Gram-negative bacteria. Methods: Pyrazole derivatives of curcumin were prepared by heating curcumin with phenyhydrazine/ substituted phenyhydrazine derivatives in AcOH. The residue was purified by silica gel column chromatography. Structures of purified compounds were confirmed by 1H NMR and Mass spectroscopy. The synthesized compounds were evaluated for their antibacterial activity by the microdilution broth susceptibility test method against gram positive (S. aureus) and gram negative (E. coli). Results: Effects of substitution in N-phenylpyrazole curcumin derivatives against S. aureus and E. coli were studied. The most active N-(3-Nitrophenylpyrazole) curcumin (12) exhibits twenty-fold more potency against S. aureus (MIC: 10μg/mL)) and N-(2-Fluoroophenylpyrazole) curcumin (5) fivefold more potency against E. coli (MIC; 50 μg/mL) than N-phenylpyrazole curcumin (4). Whereas, a remarkable decline in anti-bacterial activity against S. aureus and E. coli was observed when electron donating groups were incorporated in N-phenylpyrazole curcumin (4). Comparative studies of synthesized compounds suggest the effects of electron withdrawing and electron donating groups on unsubstituted phenylpyrazole curcumin (4). Conclusion: The structure-activity relationship (SAR) results indicated that the electron withdrawing and electron donating at N-phenylpyrazole curcumin played key roles for their bacterial inhibitory effects. The results of the antibacterial evaluation showed that the synthesized pyrazole derivatives of curcumin displayed moderate to very high activity in S. aureus. In conclusion, the series of novel curcumin derivatives were designed, synthesized and tested for their antibacterial activities against S. aureus and E. coli. Among them, N-(3-Nitrophenylpyrazole curcumin; 12) was most active against S. aureus (Gram-positive) and N-(2-Fluoroophenylpyrazole) curcumin (5) against E. coli (Gram-negative) bacteria.

scholarly journals Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4312
Author(s):  
Benjamin Lefranc ◽  
Karima Alim ◽  
Cindy Neveu ◽  
Olivier Le Marec ◽  
Christophe Dubessy ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Pharmacological Profile ◽  
Acid Moiety ◽  
Structural Determinants ◽  
Physiological Processes ◽  
Structure Activity ◽  
Peptide Derivatives ◽  
Targeting Peptide ◽  
G Protein Coupled

26RFa is a neuropeptide that activates the rhodopsin-like G protein-coupled receptor QRFPR/GPR103. This peptidergic system is involved in the regulation of a wide array of physiological processes including feeding behavior and glucose homeostasis. Herein, the pharmacological profile of a homogenous library of QRFPR-targeting peptide derivatives was investigated in vitro on human QRFPR-transfected cells with the aim to provide possible insights into the structural determinants of the Phe residues to govern receptor activation. Our work advocates to include in next generations of 26RFa(20–26)-based QRFPR agonists effective substitutions for each Phe unit, i.e., replacement of the Phe22 residue by a constrained 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid moiety, and substitution of both Phe24 and Phe26 by their para-chloro counterpart. Taken as a whole, this study emphasizes that optimized modifications in the C-terminal part of 26RFa are mandatory to design selective and potent peptide agonists for human QRFPR.

scholarly journals Structure-Activity Relationships of Sandalwood Odorants: Synthesis of a New Campholene Derivative

2010 ◽  
Vol 5 (9) ◽  
pp. 1934578X1000500
Author(s):  
Iris Stappen ◽  
Joris Höfinghoff ◽  
Gerhard Buchbauer ◽  
Peter Wolschann
Keyword(s):  
Structural Changes ◽  
Great Influence ◽  
Complete Loss ◽  
Side Chain ◽  
Side Chains ◽  
Quaternary Carbon ◽  
Structural Modifications ◽  
Structure Activity ◽  
Highly Sensitive ◽  
Sandalwood Odorants

Structural modifications of natural (-)-( Z)-β-santalol have shown that the sandalwood odor impression is highly sensitive, even to small structural changes. Particularly, the substitution of the quaternary carbon is of great influence on the scent. Epi-compounds with side chains in the endo-position possess sandalwood odor in only a few derivatives, whereas modifications at this side chain, as well as modification at the bicyclic ring systems mostly lead to a complete loss of sandalwood fragrance.

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