Penicillin antibiotic action

Sir Alexander Fleming first noted the ability of the mould P. notatum to produce an antibiotic substance (which he called penicillin) in 1928. However, he also noted that when penicillin was added to blood in vitro, it lost most of its antibiotic action, and Fleming consequently lost interest in his discovery. In the late 1930s, Howard Florey, Ernst Chain and Norman Heatley began to work on penicillin. They purified it and, unlike Fleming, studied its effect on live animals. They found that administration of penicillin to mice after their injection with lethal doses of streptococci protected the mice from an otherwise certain death. 

The introduction of the sulfa drugs was followed by the development of the penicillin antibiotics. Fleming s chance observation of the anti-bacterial action of the penicillin mold in 1928 and the subsequent isolation and identification of its active constituent by Florey and Chain in 1940 marked the beginning of the antibiotics era that still continues today. At roughly the same time, the steroid hormones found their way into medical practice. Cortisone was introduced by the pharmaceutical industry in 1944 as a drug for the treatment of arthritis and rheumatic fever. This was followed by the development of steroid hormones as the active constituents of the contraceptive pill. 

Because peptidoglycans are unique to bacterial cell walls, with no known homologous structures in mammals, the enzymes responsible for their synthesis are ideal targets for antibiotic action. Antibiotics that hit specific bacterial targets are sometimes called magic bullets. Penicillin and its many synthetic analogs have been used to treat bacterial infections since these drugs came into wide application in World War II. 

Uses Broad-spectrum antibiotic Action Bacteriostatic protein synth Spectrum Gram(+) Staphylococcus sp, Streptococcus sp Gram(-) H. pylori Atypicals Chlamydia sp, Rickettsia sp, Mycoplasma sp Dose Adults. 250-500 mg PO bid—qid Peds > 8 y. 25-50 mg/kg/24 h PO q6-12h i w/ renal/hepatic impair, w/o food preferred Caution [D, +] Contra PRG, antacids, w/ dairy products, children <8 y Disp Caps 100, 250, 500 mg tabs 250, 500 mg PO susp 250 mg/5 mL SE Photosens, GI upset, renal failure, pseudotumor cerebri, hepatic impair Interactions T Effects OF anticoagulants, cligoxin effects W/ antacids, cimeticline, laxatives, penicillin, Fe supl, dairy products effects OF OCPs EMS T Effects of anticoagulants monitor for signs of electrolyte disturbances and hypovolemia d/t D ... 

Cooper [5] reviewed early work on the binding of penicillin to a lipoprotein component in the membrane of S. aureus, and further work [Rogers, 3,62] confirms the link between penicillin binding, inhibition of mucopeptide synthesis, and the antibiotic action of penicillin. The relation of penicillin binding to penicillinase induction is less clear. 

Safety to skin is very important and protective action and cosmetic properties are also essential. These systems require the use of high concentrations of disperse phase. The vehicle may be oil-in-water (O/W) or water-in-oil (W/O) emulsion, dermatological paste and clay suspensions. Parenteral suspensions are examples with low solid content (usually 0.5-5%), except penicillin (antibiotic content > 35%). 

Fig. 7. Molecular basis for antibiotic actions of D-cycloserine and penicillin.

The clinical aspects of several antibiotics such as penicillin G, cephalosporin and many other antibiotics are summarised in Table 11.1. The potential microorganisms for the production of various antibiotics and then activities on site or mode of action of the antibiotics are also listed. 

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... 

Bacterial resistance to antibiotics has been recognized since the first drugs were introduced for clinical use. The sulphonamides were introduced in 1935 and approximately 10 years later 20% of clinical isolates of Neisseria gonorrhoeae had become resistant. Similar increases in sulphonamide resistance were found in streptococci, coliforms and other bacteria. Penicillin was first used in 1941, when less than 1 % of Staphylococcus aureus strains were resistant to its action. By 1947,3 8% of hospital strains had acquired resistance and currently over 90% of Staph, aureus isolates are resistant to penicillin. Increasing resistance to antibiotics is a consequence of selective pressure, but the actual incidence of resistance varies between different bacterial species. For example, ampicillin resistance inEscherichia coli, presumably under similar selective pressure as Staph, aureus with penicillin, has remained at a level of 30-40% for mai years with a slow rate of increase. Streptococcus pyogenes, another major pathogen, has remained susceptible to penicillin since its introduction, with no reports of resistance in the scientific literature. Equally, it is well recognized that certain bacteria are unaffected by specific antibiotics. In other words, these bacteria have always been antibiotic-resistant. 

When penicillin was first introduced as an antibiotic, the term miracle drug was coined. In 1944, it was indeed a miracle that such a wide variety of infectious diseases, from pneumonia to tetanus, could be cured by one simple chemical. Only later, when the mode of action of penicillin became partly known, did we realize that many infections were caused by similar microorganisms all of which yield to the antimetabolic action of penicillin. 

Waxman, D.J. Strominger, J. L. (1983). Penicillin-binding proteins and the mechanism of action of B-lactam antibiotics. Annu. Rev. Biochem. 52, 825-869. 

Much information on the mechanism of action and cross-resistance of purine analogues has been obtained in bacteria, some of which are quite sensitive to certain of these compounds in vitro. There is a great deal of variation in response of the various bacteria to a particular agent and of a particular bacterium to the various cytotoxic purine analogues. Some, if not most, of these differences are probably due to differences in the anabolism of the various compounds. Despite the fact that certain purine analogues have quite a spectrum of antibacterial activity in vitro, none has been useful in the treatment of bacterial infections in vivo because their toxicity is not selective—the metabolic events whose blockade is responsible for their antibacterial activity are also blocked in mammalian cells and thus inhibition of bacterial growth can only be attained at the cost of prohibitive host toxicity. In contrast, the sulpha drugs and antibiotics such as penicillin act on metabolic events peculiar to bacteria. 

An additional disadvantage with many penicillin and cephalosporin antibiotics is that bacteria have developed resistance to the drugs by producing enzymes capable of hydrolysing the P-lactam ring these enzymes are called P-lactamases. This type of resistance still poses serious problems. Indeed, methicillin is no longer used, and antibiotic-resistant strains of the most common infective bacterium Staphylococcus aureus are commonly referred to as MRSA (methicillin-resistant Staphylococcus aureus). The action of P-lactamase enzymes resembles simple base hydrolysis of an amide. 

Note that penicillins and structurally related antibiotics are frequently deactivated by the action of bacterial -lactamase enzymes. These enzymes also contain a serine residue in the active site, and this is the nucleophile that attacks and cleaves the P-lactam ring (see Box 7.20). The P-lactam (amide) linkage is hydrolysed, and then the inactivated penicillin derivative is released from the enzyme by further hydrolysis of the ester linkage, restoring the functional enzyme. The mode of action of these enzymes thus closely resembles that of the serine proteases there is further discussion in Box 7.20. 

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