Class of antibiotics

In general, penicillins exert thek biological effect, as do the other -lactams, by inhibiting the synthesis of essential structural components of the bacterial cell wall. These components are absent in mammalian cells so that inhibition of the synthesis of the bacterial cell wall stmcture occurs with Htde or no effect on mammalian cell metaboHsm. Additionally, penicillins tend to be kreversible inhibitors of bacterial cell-wall synthesis and are generally bactericidal at concentrations close to thek bacteriostatic levels. Consequently penicillins have become widely used for the treatment of bacterial infections and are regarded as one of the safest and most efficacious classes of antibiotics. 

Resistance to Tetracyclines. The tetracyclines stiU provide inexpensive and effective treatment for several microbial infections, but the emergence of acquired resistance to this class of antibiotic has limited their clinical usehilness. Studies to define the molecular basis of resistance are underway so that derivatives having improved antibacterial spectra and less susceptibiUty to bacterial resistance may be developed. Tetracyclines are antibiotics of choice for relatively few human infections encountered in daily clinical practice (104), largely as a result of the emergence of acquired tetracycline-resistance among clinically important bacteria (88,105,106). Acquired resistance occurs when resistant strains emerge from previously sensitive bacterial populations by acquisition of resistance genes which usually reside in plasmids and/or transposons (88,106,107). Furthermore, resistance deterrninants contained in transposons spread to, and become estabUshed in, diverse bacterial species (106). 

Figure 6.1 The chemical structure of some members of the important classes of antibiotics.

You should have concluded that because these structures are very diverse, it is unlikely that they will act in the same way. This is, in fact, true the mode of action differs from one class of antibiotics to another. We have listed some modes of action of antibiotics in Table 6.1. 

When written in this form, it should be apparent that penicillins can be diversified by substituting different groups in place of R. The penicillin class of antibiotics does, in fact, contain members that have different R groups. We will examine these later in the chapter and describe the strategies used to generate penicillins with different substitutions. 

Batt AL, Aga DS (2005) Simultaneous analysis of multiple-classes of antibiotics by ion trap LC/MS/MS for assessing surface water and groundwater contamination. Anal Chem 77 2940-2947... 

Studies on the mode of action of the penicillins in inhibiting bacterial cell-wall biosynthesis suggest that the members of this class of antibiotics (including the closely related cephalosporins) are conformationally restricted substrate analogs... 

Before eonsidering specific mechanisms of resistance for particular classes of antibiotic it is worth considering potential mechanisms of resistance in bacterial cells. These are summarized in Fig. 9.1 and specific examples are listed in Table 9.3. 

The following sections describe the biochemical mechanisms of resistance to different classes of antibiotics, with the antibiotics grouped according to their mechanism of action. 

Three types of resistance mechanism have also been identified with this class of antibiotic (Chopra etal. 1992). 

These three classes of antibiotics are often grouped together because of their similar mode of action. They share a common mechanism of resistance, but there are some mechanisms specific to each group (Leclerq Courvalin 1991). 

Strains of Streptomyces isolated from a range of nrban, agricnltnral, and forest soils isolated on a standard medinm displayed resistance to antibiotics that were well established in clinical practice. Resistance was fonnd among all classes of antibiotics, and a distnrbing nnmber of isolates were resistant to between 5 and 10 of them (D Costa et al. 2006). 

Example. Kanamycin is a member of the aminoglycoside class of antibiotics, all of which are eliminated exclusively by glomerular filtration. Creatinine is a natural body substance that is cleared almost exclusively by glomerular filtration, and creatinine clearance rate is frequently used as a diagnostic tool to determine glomerular filtration rate. The relationship... 

Cephalosporins are a class of antibiotic produced via the intermediate 7-aminocephalos-poranic acid (7-ACA), or 7-aminodesacetoxycephalosporanic acid (7-ADCA). Directed evolution has been used to improve the activity of cephalosporin acylases to produce these intermediates from adipyl-7-ACA or cephalosporin C [68]. Using site-directed saturation mutagenesis and a selection system whereby the E. coli host is dependent on leucine liberated from derivatives of the cephalosporin side-chains, a mutant was found that increased the catalytic efficiency toward adipyl-7-ADCA by 36-fold. 

Lactams are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, carbapenems, and clavams (/8-lactamase inhibitors). The metabolic engineering of penicillin and cephalosporins production has been summarized by several good reviews [71,72], so the focus here is clavulanic acid, which has attracted interest in recent years. 

Class of antibiotics Name of the most commonly used antibiotic Use... 

The natural products Mycoticin A (22, R = H) and B (22, R = Me) belong to the skipped-polyol-polyene class of antibiotics. Our analytical interest here is to use this very complex molecular structure to demonstrate some of the tools employed, mainly for the elucidation of the polyene part of the molecule. This family of polyene macrolide class was discovered in 195045 with the finding of Nystatin (23), which is produced by the Streptomyces bacteria. The exact structure was elucidated only in 1970 by Chong and Rickards46 and, in 1971, Nystatin Ai (23) and A2 (not shown in this review) were separated. 

The p-lactams, mainly penicillins and cephalosporins, are by production volume the most important class of antibiotics worldwide, enjoying wide applicability towards a range of infectious bacteria. Most of the key molecules are semi-synthetic products produced by chemical modification of fermentation products. Production of these molecules has contributed significantly to the development of large-scale microbial fermentation technology, and also of large-scale biocatalytic processing. 

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

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