Antibacterials inactivation

In those eases where concurrent use is thought neeessary, it has been recommended that the serum levels of both antibacterials elosely monitored. However, note that antibacterial inactivation can continue in the assay sample, and one author suggests that rapid assay is necessary, while others note the importance of protecting samples against further inactivation. 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

Studies on the mechanism of action of /3-lactam antibiotics have shed considerable light on how these agents kill bacteria. They also help explain qualitative differences between various agents and why there is a correlation between the reactivity of the /3-lactam and antibacterial activity. However, it is also clear that reactivity is only one factor in determining how effectively a given /3-lactam antibiotic will inactivate bacterial enzymes (82BJ(203)223). 

Plasmid- ortransposon-mediated resistance occurs by inactivation ofthe antibiotic. Fosfomycin is combined with glutathione intracellularly to produce a compound lacking in antibacterial activity. The gene encoding the enzyme catalysing this reaction has been designated/or-r. 

The biological activity of a compound can often be affected dramatically by the presence of even a single fluorine substituent that is placed in a particular position within the molecule. There are diverse reasons for this, which have been discussed briefly in the preface and introduction of this book. A few illustrative examples of bioactive compounds containing a single fluorine substituent are given in Fig. 3.1. These include what is probably the first example of enhanced bioactivity due to fluorine substitution, that of the corticosteroid 3-1 below wherein Fried discovered, in 1954, that the enhanced acidity of the fluorohydrin enhanced the activity of the compound.1 Also pictured are the antibacterial (3-fluoro amino acid, FA (3-2), which acts as a suicide substrate enzyme inactivator, and the well-known anti-anthrax drug, CIPRO (3-3). 

Currently, all donors and blood preparations undergo multistage and expensive control to ensure the absence of viral contamination In this respect, the development of affordable methods of inactivation of viruses could be an important step toward safety in hemotransfusion. Currently used treatments such as UV irradiation damage therapeutic components of the blood (Williamson and Cardigan, 2003), so alternative selective approaches are needed for this purpose. Among them, chemotherapy, photochemotherapy (PCT), and photodynamic antibacterial therapy should be noted (Mohr, 2000). 

Fig. 5.4. Inactivation of /3-lactamases by cephalosporins (Fig. 5.1, Pathway b). The mechanism of this inactivation is similar to that of class-II inhibitors (Fig. 5.3, Pathway b) and is based on the slow hydrolysis of the acyl-enzyme complex (Pathway b). The normal deacylation of the acyl-enzyme complex represented by Pathway a results in the lost of antibacterial activity of the drug. The ratio between Pathways a and b is determined by the nature of the...

Like other semisynthetic penicillins, methicillin exhibits an antibacterial effect similar to that of benzylpenicillin. The main difference between methicillin and benzylpenicillin is that it is not inactivated by the enzyme penicillinase, and therefore it is effective with respect to agents producing this enzyme (staphylococci). It is used for infections caused by benzylpenicillin-resistant staphylococci (septicemia, pneumonia, empyemia, osteomyelitis, abscesses, infected wounds, and others). Synonyms of this drug are cinopenil, celbenin, staphcillin, and others. 

Clavulanic acid is isolated from Streptomyces clavuligerus [60-66], and sulbactam, a sulfone of penicillanic acid, is synthesized from 6-APA [67-69], Both compounds have extremely weak antibacterial properties and act by forming irreversible complexes with beta-lactamase, which inactivates the enzyme, and as a result the beta-lactam antibiotic has time to destroy the microorganism. Currently, a number of combined drugs containing various combinations of beta-lactamase antibiotics and inhibitors are used. 

Antibacterial activity of macrolides depends on the acidity of the medium. High activity is observed in neutral and basic media in comparison with acid. In particular, erythromycin is inactivated in the acidic medium of the stomach. Macrolides have a relatively broad spectrum of use, and they are active with respect to Gram-positive and Gram-negative microorganisms, achiomycetes, mycoplasma, spirochaeta, chlamydia. Bacteria Rickettsia, certain mycobacteria. Colon bacillus, blue-pus bacillus, shigella, salmonella, and so on. 

Mechanism of Action An antibacterial UTI agent that inhibits the synthesis of bacterial DNA, RNA, proteins, and cell walls by altering or inactivating ribosomal proteins. Therapeutic Effect Bacteriostatic (bactericidal at high concentrations). Pharmacokinetics Microcrystalline form rapidly and completely absorbed macrocrystalline form more slowly absorbed. Food increases absorption. Protein binding 40%. Primarily concentrated in urine and kidneys. Metabolized in most body tissues. Primarily excreted in urine. Removed by hemodialysis. Half-life 20-60 min. 

These substances resemble 3-lactam molecules (Figure 43-7) but they have very weak antibacterial action. They are potent inhibitors of many but not all bacterial 3 lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. -Lactamase inhibitors are most active against Ambler class A lactamases (plasmid-encoded transposable element [ ] lactamases in particular), such as those produced by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E coli, and pneumoniae. They are not good inhibitors of class lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal 3 lactamases of bacteroides and moraxella. 

Penam Sulfone p-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of /i-lactainase inhibitors based on the readily accessible penicillin nucleus. An early success was peni-cillanic acid sulfone, (2(5)-ru)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-azabicyclo [3.2.0]heptane-2-carboxylic acid (sulbactam) (R = R1 = H,R2 = R = CH3), CsHnNOjS. The synthesis, microbiology, and clinical use of sulbactam have been reviewed. Sulbactam, with minor exceptions, is a weak antibacterial, but is a potent irreversible inactivator of many /3 lactamases, including penases and Richmond Sykes type 11, III, IV. V, and VI (Bactcroides) /3-lactamases. Sulbactam is better than clavulanic acid against type I Cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sul-fones have been reported to be /3-lactamase inhibitors. 

Structure—Activity Relationships. Biological evaluation of penicillins yields information such as in vitro and in vivo antibacterial activities, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), protective effectiveness in laboratory animals (PD50), and pharmacokinetic characteristics including efficiency of absorption, serum levels, tissue distribution, urinary excretion, recycling, etc. Penicillins are also tested for ability to resist inactivation by (S-lactamase produced by both gram-positive and gram-negative bacteria,... 

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