Antibacterials aminoglycosides

An enzyme that catalyses ATP-dependent 2 -phosphorylation and acetyl-CoA-dependent 6 -acetylation of the antibacterial aminoglycosides has been reported.260 Because of its complementary spectrum of two enzymic reactions, this bifunctional enzyme has a wide breadth of activity. Pentacoordinated thiophosphorane intermediates such as (292a) and (292b) are involved in the hydrolytic reactions of the monothioate analogues of 5 -O-methyluridine 2 - and 3 -dhnethylphosphates, (293) and (294), which have been studied over a wide range of HC1 acidities, //<, = —1.7 to pH9.261... 

Due to the great number of functional groups and asymmetric centres, only a small portion of the possible structural variations has been synthesised and tested until now. The structural variety of antibacterial aminoglycosides makes it difficult to present a comprehensive picture for the structure-activity relationships. 

General Antibacterial Properties. In the clinical control of bacterial infectious disease, the aminoglycosides gentamicin, tobramycin, amikacin, netilmicin, and to a lesser extent, dibekacin and isepamicin are most commonly used for the treatment of serious infections involving aerobic or facultative gram-negative baciUi, especially in the compromised host. This usage is discussed in the Hterature (44—51). 

Members of the aminoglycoside class of antibacterial antibiotics retain an important role in the control of bacterial infectious disease, especially in... 

Norfloxacin (1, R = C2H5, R = H), a typical example, exhibits broad-spectrum activity and is useful in the treatment of upper respiratory tract and urinary infections [7] Lomefloxacin (2), a very recent introduction, is a third-generation product that, given once daily, is especially useful against pathogens resistant to cephalosponns, penicillins, and aminoglycosides [4] Floxacillin (J) is a stable, orally active antibacterial with improved activity over thenonfluonnated product (cloxacillin) [5]... 

The in vivo protective activity of rifaximin was studied in mice, infected experimentally by intraperitoneal inoculation of S. aureus Colliva and compared to that of rifampicin (a systemic rifamycin) and gentamicin (a poorly absorbed aminoglycoside) [74]. After oral administration, only rifampicin was effective whereas the other two compounds were inactive at doses up to 10 mg/kg. However, when injected subcutaneously, rifaximin displayed a good therapeutic efficacy (table 2). While confirming its antibacterial activity, these results clearly indicate that rifaximin, like gentamycin, is poorly absorbed after oral administration. 

Tetracyclines, macrolides, and aminoglycosides are important classes of antibacterials... 

The discovery of a novel structural class of antibacterials is notable, as these are few and far between. The sulfa drugs, p-lactams, quinohnes, tetracyclines, macrohdes, and aminoglycosides have been around for decades. Multiple improvements have been made over time in each of these classes but without breaking out into new structural classes. There are two notable, recent examples of new stractural classes of antibacterials and these are worth knowing about. 

Other key classes of antibacterials include the tetracyclines (Aureomycin, Terramycin), macrolides (erythromycin, Zithromax, Biaxin), and aminoglycosides (streptomycin, amikacin, neomycin). These antibacterials are protein synthesis inhibitors. 

Aminoglycoside a structurally complex antibacterial that works as bacterial protein synthesis inhibitor. 

The quinolone antibiotics feature as the one main gronp of antibacterial agents that is totally synthetic, and not derived from or based upon natural products, as are penicillins, cephalosporins, macrolides, tetracyclines, and aminoglycosides. The first of these compounds to be employed clinically was nalidixic acid more recent drugs in current use include ciprofloxacin, norfloxacin, and ofloxacin... 

The biochemical mode of action of the aminoglycosides as antibacterials has long been a topic of great interest. Early experiments carried out soon after the introduction of streptomycin suggested a variety of modes of action, but these conclusions were based largely on symptomatic analyses of antibiotic-treated bacterial cultures. One important experiment done in 1948 showed that streptomycin blocks enzyme indnction in susceptible bacteria this was the closest that anyone came to identifying the mechanism of action at the time. 

Aminoglycoside resistance has been a powerful impediment to the continued use of these potent antibacterial agents. The myriad of strategies that confer resistance... 

AND ANTIBACTERIAL ACTIVITY OF KANAMYCIN AND NEOMYCIN CLASS AMINOGLYCOSIDE ANTIBIOTICS... 

It has been shown that the stereochemistry of the glycosidic bond to which the carbohydrate component is attached at the neamine core is essential for antibacterial activity. The neomycin class aminoglycoside consists of a neamine core and a P-linked carbohydrate component attached at the 0-5 position, while the kanamycin class aminoglycoside consists of a neamine core with a-linked carbohydrate component attached at the 0-6 position. Since neamine is the pivotal component of both neomycin and kanamycin, a readily accessible library of nnnsnal sugars will provide opportunity for the facile construction of both classes of aminoglycosides via glycosylation approach. 

By employing a 27-nucleotide RNA that represents the binding site of aminoglycoside toward the 16S rRNA, it has been found that neamine binds to such an rRNA sequence in a 2 1 ratio. Several neamine dimers were then constructed to investigate their antibacterial activity and their capability to resist or inhibit the action of AME (Scheme 4.25). These neamine dimers displayed modest to excellent antibacterial activity (Table 4.16). In addition, these dimers have also been noted for their inhibitory effect against AAC(6 )-APH(2"). 

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