Lactams antibacterial activity

Antibiotics have a wide diversity of chemical stmctures and range ia molecular weight from neat 100 to over 13,000. Most of the antibiotics fall iato broad stmcture families. Because of the wide diversity and complexity of chemical stmctures, a chemical classification scheme for all antibiotics has been difficult. The most comprehensive scheme may be found ia reference 12. Another method of classifyiag antibiotics is by mechanism of action (5). However, the modes of action of many antibiotics are stiU unknown and some have mixed modes of action. Usually within a stmcture family, the general mechanism of action is the same. For example, of the 3-lactams having antibacterial activity, all appear to inhibit bacterial cell wall biosynthesis. 

In common with the naturally occurring carbapenem thienamycin (2), the introduction of the /n j -6-[l-(R)-hydroxyethyi] group had a profound effect on the biological properties of the penems. This, together with an indication from an early study (93) that, as with other P-lactams, the 5(R)-enantiomer was solely responsible for antibacterial activity, provided impetus for the development of methods for the synthesis of chiral penems. 

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. 

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

Isothiazole substituents have been attached to /3-lactam antibiotics and to macrocyclic antibiotics such as erythromycin. The sulfa drug, Sulfasomizole (244) also has good antibacterial activity. Thiosemicarbazones of 5-formyl- and 5-acetylisothiazoles show high activity against the pox group of viruses (65AHC(4)107). 

One of the major differences between penicillins and cephalosporins is the possibility for a concerted elimination of the C-3 substituent in the case of cephalosporins (6->7). There is now considerable evidence to support the idea that an increase in the ability of the C-3 substituent to act as a leaving group results in an increased reactivity of the 8-lactam carbonyl (75JMC408). Thus, both the hydrolysis rate of the 8-lactam and 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). 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

Modification at the C(7) position of the penam ring system (other than ring opening reactions) has not been extensively studied. It was possible, however, to convert the /3-lactam to a /3-thionolactam in 1% yield as shown in Scheme 55 (75JA5628). The deblocking product (73) had greatly reduced antibacterial activity compared to the parent /3-lactam. 

Closely related to the penicillins are the cephalosporins, a group of /3-lactam antibiotics that contain an unsaturated six-membered, sulfur-containing ring. Cephalexin, marketed under the trade name Keflex, is an example. Cephalosporins generally have much greater antibacterial activity than penicillins, particularly against resistant strains of bacteria. 

Boyd DB, Herron DK, Lunn WHW, Spitzer WA. Parabolic relationships between antibacterial activity of cephalosporins and beta-lactam reactivity predicted from molecular orbital calculations. / Am Chem Soc 1980 102 1812-14. 

The 1,2,4-thiadiazole moiety has been incorporated in (3-lactam antibacterials to modulate pharmacokinetic properties and more recently into a cephalosporin. The cephalosporin 129 displays a good balance of serum stability and in vitro activity. The cephalosporin derivative 48 (see Section 5.08.7.4) also shows good pharmacokinetic properties <2001JAN364>. 

Lactam antibiotics have several stereogenic centers, the configurations of which are critical for antibacterial activity. In the following section, some examples that illustrate stereochemical aspects of the hydrolytic degradation of /1-lactams are presented. 

APA), comprised of a thiazolidine and a 4-membered 3-lactam ring, 6-APA itself lacks antibacterial activity. 

Finally, the most important mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamase by the bacteria. Beta-lactamases break the C-N bond in the beta-lactam ring of antibiotics. Since its existence is absolutely necessary for reacting with PBP, a break in the beta-lactam ring leads to a loss of antibacterial activity. 

The cephalosporin nucleus is synthesized with a beta-lactam ring attached to a six-membered dihydrothiazine ring. Unlike the penicillin nucleus, the cephalosporin nucleus is much more resistant to beta-lactamase. Moreover, it has large areas for possible modifications. Modifications Rj in the acyl side chain alter the antibacterial activity, while modifications of R2 are associated with changes in the pharmacokinetics and metabolic parameters of the drug. 

Beta-lactamase inhibitors include clavulanic acid, sulbactam and tazobactam. They are structurally related to the beta-lactam antibiotics however the antibacterial activity of these compounds is very weak or negligible. They are strong inhibitors of bacterial beta-lactamases and can protect beta-lactam antibiotics from hydrolysis by these enzymes. 

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