Inactivation antibiotics

Fig. 9.1 Schematic representation of possible mechanisms of resistance in Gram-negative and Gram-positive bacteria. 1, antibiotic-inactivating enzymes 2, antibiotic efflux proteins 3, alteration or duplication of intracellular targets 4, alteration of the cell membrane reducing antibiotic uptake 5, alterations in porins or lipopolysaccharide reducing antibiotic uptake or binding.

Several enzymes have important therapeutic and other medical or pharmaceutical uses (Table 25.3). In this section, those enzymes used therapeutically will be described, with section 4 discnssing the applications of microbially derived enzymes for antibiotic inactivation in sterility testing and diagnostic assays. 

The three-dimensional structure of the aminoglycosides plays an essential role in their interaction with both RNA and the enzymes involved in the antibiotic inactivation and thus determines their biological function. A proper understanding of the different factors that govern aminoglycoside-RNA/protein interactions requires a detailed knowledge of the three-dimensional structure, and conformational properties of these oligosaccharides in both the... 

In addition to transpeptidases, other penicillin-binding proteins (PBPs) function as transglycosylases and carboxypeptidases. All of the PBPs are involved with assembly, maintenance, or regulation of peptidoglycan cell wall synthesis. When (3-lactam antibiotics inactivate PBPs, the consequence to the bacterium is a structurally weakened cell wall, aberrant morphological form, cell lysis, and death. 

Both pirlimycin and its sulfoxide metabolite were partially converted to ribonucleotide adducts by gastrointestinal tract microflora and excreted in feces. Such adducts have been well documented as products of antibiotic inactivation by bacteria for a variety of substances including lincomycin and clindamycin (117-119). 

Drug resistance may be mediated by a variety of mechanisms, such as lack of or an alteration in a target site, lowered penetrability of the drug due to decreased permeability, or increased efflux or presence of antibiotic-inactivating enzymes (Table 28.1). 

Inactivation (chromosomally mediated) -Lactamase-susceptible /J-Lactams Antibiotic inactivation... 

Mechanism or resistance (1) Antibiotic inactivation (2) Efflux Does not occur Occurs by membrane transporters... 

Antibiotic resistance can be the result of several molecular mechanisms (Table 1). Some of the most important of these mechanisms include enzyme-catalyzed antibiotic inactivation or modification, altered transport such as efflux, and others such as metabolic bypass and sequestration. Each of these mechanisms requires the synthesis of associated proteins to mediate resistance. These are often highly specialized and efficient, and frequently the corresponding genes can be acquired on mobile... 

Table 7.20. R FACTOR MEDIATED ANTIBIOTIC INACTIVATING ENZYMES REPORTED FROM STRAINS OF PS. AERUGINOSA...

The generation of these ribonucleotide adducts are believed to be the result of GI Tract microfloral activity and not enzymatic/metabolic transformations in the cow itself. Such adducts have been well documented as products of antibiotic inactivation produced by various strains of Streptomyces and Staphylococci for a variety of substances such as the lincosaminides (8-11), spectinomycin (12) and streptomycin (13). Furthermore, we have been able to generate pirlimycin 3-(5 -adenylate) by simply incubating pirlimycin with fresh cow manure from untreated cows, although the organisms involved have not been characterized. 

Ozanne, B. Benveniste, R. Tipper, D. Davies, J. Aminoglycoside antibiotics inactivation by phosphorylation in Escherichia coli carrying R factors. J. BacterioL, 100, 1144-1146 (1969)... 

Benveniste R, Davies J. Aminoglycoside antibiotic inactivating enzymes in actinomycetes similar to those present in clinical isolates of arttibiotic resistant bacteria. Proc Natl Acad... 

Some nonproteinogenic amino acids, produced enzymatically, are shown in Table 29.4 for example, L-homophenylalanine, a key intermediate of levetiracetam and brivaracetam applicable as antiepileptic drugs, or D-fluoroalanine, a key intermediate of antibiotics inactivating the bacterial D-alanine transaminase. In Table 29.4 a selection of proteinogenic and nonproteinogenic amino acids, the used biocatalysts, synthesis strategies, and the substrates used are listed. 

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