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

Mechanism of Action of Antimicrobial Agents

2019 ◽  
Author(s):  
Ruaridh Buchanan ◽  
Armine Sefton
Keyword(s):  
Cell Wall ◽  
Cell Membrane ◽  
Cellular Structure ◽  
Antimicrobial Agents ◽  
Cell Integrity ◽  
Beta Lactam ◽  
Selective Toxicity ◽  
Fungal Cell ◽  
Lactam Ring ◽  
Membrane Target

Antibacterial and antifungal agents aim to kill pathogens, or at the very least incapacitate them. To achieve this aim these agents must have a reasonable degree of toxicity at the cellular level. If this toxicity was equally manifest against all cell types then the drugs would be unusable in patients as the side effect profile would be unacceptably severe. Selective toxicity, whereby the agents are orders of magnitude more toxic to bacteria or fungi than human cells, allows for the safe and effective administration of these agents to patients. There are a number of different mechanisms by which an antimicrobial agent can yield selective toxicity: ● Target a cellular structure that exists only in bacteria/fungi—e.g. the cell wall; ● Target a cellular structure that has a significantly different structure in bacteria/ fungi— e.g. the ribosome; the fungal cell membrane; ● Target cellular enzymes that are significantly different in bacteria/fungi e.g. topoisomerase; ● Target a synthetic pathway that exists only in bacteria e.g. folate synthesis. Broadly, antibacterial drugs can be divided into the following categories: ● Agents that target the cell wall; ● Agents that target the cell membrane; ● Agents that inhibit protein synthesis; ● Agents that inhibit DNA replication/ transcription of RNA; ● Agents that target folate synthesis; ● Agents that directly damage intracellular structures. The cell wall is unique to bacteria, and therefore an ideal target. Disrupting the complex cross-linking process required to produce the cell wall leads to loss of bacterial cell integrity and therefore to cell death. The following classes of antibiotics target the cell wall: The first class to be discovered, and still in many cases the most effective, incorporates the four-membered beta-lactam ring—its homology to d-alanyl-d-alanine allows beta-lactam-containing compounds to bind to cell wall peptidoglycans and act as chain terminators. The beta-lactam ring is fused to a five-membered sulphur-containing ring. Variations in side chains account for the differing pharmacokinetics and spectra of action of the different compounds—for example, the addition of an amino group to benzylpenicillin produces ampicillin.

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.

Pivmecillinam (selexid)

1978 ◽  
Vol 16 (26) ◽  
pp. 103-104
Keyword(s):  
Cell Wall ◽  
Bacterial Cell ◽  
Bacterial Cell Wall ◽  
Side Chain ◽  
Lactam Ring

Mecillinam and pivmecillinam are the first of a new group of penicillins, the amidino penicillins, which differ from other penicillins in having the side chain joined to the β-lactam ring by a β-amidino group rather than a β-acylamino group. The amidino group gives it properties quite different from other β-lactam antibiotics including the cephalosporins and other penicillins, and unlike them it acts on only one enzyme in the biosynthesis of the bacterial cell wall.

Characteristics of Aerobacter beta-lactamase

1968 ◽  
Vol 14 (2) ◽  
pp. 139-145 ◽  
Author(s):  
M. Goldner ◽  
D. G. Glass ◽  
P. C. Fleming
Keyword(s):  
Reaction Rates ◽  
Penicillin G ◽  
Cephalosporin C ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Lactam Ring ◽  
Rate Of Hydrolysis ◽  
High Concentrations ◽  
Hydrolysis Of ◽  
Pseudomonas Pyocyanea

In this investigation, Aerobacter cloacae is shown to inactivate cephalosporin by hydrolysis of its beta-lactam ring. This was demonstrated by iodine absorption and infrared absorption spectra.The values of the Michaelis constant obtained with cephalosporin C and deacetyl cephalosporin C indicate a great affinity of the Aerobacter's beta-lactamase for its substrate. The enzyme was most active at pH 7.0 and 37 C. Aqueous washings of the Aerobacter cells were a potent source of enzyme.The beta-lactamase of A. cloacae was active on both cephalosporin and penicillin. A higher rate of hydrolysis was observed with cephalosporin C and deacetyl cephalosporin C than with cephalothin and cephaloridine. The ratio of reaction rates on cephalosporin C to that on penicillin G was consistently of the order of 100 to 1. The activity on V, N, and especially the semisynthetic penicillins was also low.The A. cloacae enzyme was easily demonstrable in large amount without added inducer. By contrast, the activity of the beta-lactamase from Pseudomonas pyocyanea cannot be detected unless high concentrations of inducer are used.

scholarly journals Role of Penicillin-Binding Protein 2 (PBP2) in the Antibiotic Susceptibility and Cell Wall Cross-Linking of Staphylococcus aureus: Evidence for the Cooperative Functioning of PBP2, PBP4, and PBP2A

2005 ◽  
Vol 187 (5) ◽  
pp. 1815-1824 ◽  
Author(s):  
Tomasz A. Łęski ◽  
Alexander Tomasz
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Antimicrobial Agents ◽  
Binding Protein ◽  
Resistant Mutant ◽  
Site Directed Mutagenesis ◽  
Cross Linking ◽  
Penicillin Binding Protein ◽  
Beta Lactam ◽  
Experimental Proof

ABSTRACT Ceftizoxime, a beta-lactam antibiotic with high selective affinity for penicillin-binding protein 2 (PBP2) of Staphylococcus aureus, was used to select a spontaneous resistant mutant of S. aureus strain 27s. The stable resistant mutant ZOX3 had an increased ceftizoxime MIC and a decreased affinity of its PBP2 for ceftizoxime and produced peptidoglycan in which the proportion of highly cross-linked muropeptides was reduced. The pbpB gene of ZOX3 carried a single C-to-T nucleotide substitution at nucleotide 1373, causing replacement of a proline with a leucine at amino acid residue 458 of the transpeptidase domain of the protein, close to the SFN conserved motif. Experimental proof that this point mutation was responsible for the drug-resistant phenotype, and also for the decreased PBP2 affinity and reduced cell wall cross-linking, was provided by allelic replacement experiments and site-directed mutagenesis. Disruption of pbpD, the structural gene of PBP4, in either the parental strain or the mutant caused a large decrease in the highly cross-linked muropeptide components of the cell wall and in the mutant caused a massive accumulation of muropeptide monomers as well. Disruption of pbpD also caused increased sensitivity to ceftizoxime in both the parental cells and the ZOX3 mutant, while introduction of the plasmid-borne mecA gene, the genetic determinant of the beta-lactam resistance protein PBP2A, had the opposite effects. The findings provide evidence for the cooperative functioning of two native S. aureus transpeptidases (PBP2 and PBP4) and an acquired transpeptidase (PBP2A) in staphylococcal cell wall biosynthesis and susceptibility to antimicrobial agents.

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 Cephalosporins : An imperative antibiotic over the generations

2020 ◽  
Vol 11 (1) ◽  
pp. 623-629
Author(s):  
Aiswarya P. Nath ◽  
Arul Balasubramanian ◽  
Kothai Ramalingam
Keyword(s):  
Cell Wall ◽  
Bacterial Cell ◽  
Bacterial Cell Wall ◽  
Cell Wall Synthesis ◽  
Beta Lactam ◽  
Oral Formulations ◽  
Lactam Ring ◽  
Cephalosporin Antibiotics ◽  
New Generation ◽  
Infectious Organism

Cephalosporins are the most commonly prescribed class of antibiotics, and its structure and pharmacology are similar to that of penicillin. It's a bactericidal, and its structure contains beta-lactam ring, as like of penicillin, which intervenes in bacterial cell wall synthesis. Cephalosporins are derived from the mold Acremonium (previously called as Cephalosporium). It was first discovered in 1945; scientists have been improving the structure of cephalosporins to make it more effective against a wider range of bacteria. Whenever the structure of cephalosporins modified, a new "generation" of cephalosporins are made. So far, there are five generations of cephalosporins available. They are prescribed against various organisms and infections. The cephalosporin antibiotics interfere with cell-wall synthesis of bacteria, leading to the breakdown of the infectious organism. To achieve this effect, the antibiotic must cross the bacterial cell wall and bind to the penicillin-binding proteins. Various generations of cephalosporins, mechanisms of resistance, pharmacokinetics, adverse reactions, and their clinical use were reviewed in this article. Most of the cephalosporins are available as parenteral, but the oral formulations are also available for certain drugs. Rather than learn all cephalosporins, it is reasonable for the clinician to be familiar with selected cephalosporins among the parenteral and oral formulations.

Rapid Screening Assay for Beta-Lactam Antibiotics in Milk: Collaborative Study

1982 ◽  
Vol 65 (5) ◽  
pp. 1186-1192 ◽  
Author(s):  
Stanley E Charm ◽  
Ruey K Chi ◽  
◽  
H Bryant ◽  
M Carson ◽  
...  
Keyword(s):  
Cell Wall ◽  
Control Point ◽  
Collaborative Study ◽  
Rapid Screening ◽  
Penicillin G ◽  
Beta Lactam ◽  
Screening Assay ◽  
Milk Samples ◽  
Beta Lactam Antibiotics ◽  
The Mean

Abstract A 15 min assay for beta-lactam antibiotics has been used by dairies for several years as a screening procedure for testing milk tankers before they unload. The test is based on a competition between 14C-penicillin and beta-lactam antibiotics in the milk samples for sites on a microbial cell wall that specifically binds beta-lactam. In a collaborative study, 11 laboratories correctly distinguished 10 coded zero penicillin G samples and 10 coded 0.01 IU/mL samples. The proposed test is qualitative, positive or negative, and can detect the presence of beta-lactam antibiotics at the 0.01 IU/mL level. The control point for determining positive or negative samples is more than 3 standard deviations from the mean of 0.01 IU/mL. The method has been adopted official first action.

scholarly journals Interactions between active-site-serine β-lactamases and compounds bearing a methoxy side chain on the α-face of the β-lactam ring: kinetic and molecular modelling studies

1993 ◽  
Vol 293 (3) ◽  
pp. 607-611 ◽  
Author(s):  
A Matagne ◽  
J Lamotte-Brasseur ◽  
G Dive ◽  
J R Knox ◽  
J M Frère
Keyword(s):  
Water Molecule ◽  
Molecular Modelling ◽  
Side Chain ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Class A ◽  
Molecular Modelling Studies ◽  
Lactam Ring ◽  
Modelling Studies

The interactions between three class A beta-lactamases and compounds bearing a methoxy side chain on the alpha-face of the beta-lactam ring (cefoxitin, moxalactam and temocillin) have been studied. When compared with the situation prevailing with good substrates, both acylation and deacylation steps appeared to be severely impaired. Molecular modelling studies of the structures of the Henri-Michaelis complexes and of the acyl-enzymes indicate a major displacement of the crystallographically observed water molecule which connects the glutamate-166 and serine-70 side chains and underline the role of this water molecule in both reaction steps.

Sign in / Sign up

Export Citation Format

Share Document