CONTROL OF MOS BY ANTIBIOTICS & OTHER CHEMOTHERAPEUTIC AGENTS..
1.) INHIBITION OF CELL WALL SYNTHESIS:
Antibiotics such as penicillins, cephalosporins, cycloserine, vancomycin, & bacitracin inhibits the biosynthesis of Peptidoglycan.
- Penicillin: They are classes of beta-lactam antibiotics(are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam ring in their molecular structures) which acts against Gram positive, some spirochetes & Gram negative diplococci. Penicillin was first discovered by Alexander Fleming in 1928 from Penicillium notatum .All the penicillin have basic structure of B-lactam nucleus & several attached groups. It blocks the cross linking of carbohydrate in peptidoglycan. This causes the formation of weak wall & thus the cell swells & bursts.( http://en.wikipedia.org/wiki/Beta-lactam_antibiotic http://en.wikipedia.org/wiki/Beta-lactamase)
Penicillin is produced from Penicillium notatum & P.chrysogenum.MODE OF ACTION:Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. β-Lactam antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall; this is achieved through binding of the four-membered β-lactam ring of penicillin to the enzyme DD-transpeptidase. Consequently, DD-transpeptidase cannot catalyze formation of these cross-links, and an imbalance between cell wall production and degradation develops, causing the cell to rapidly die.More specifically, the enzymes that hydrolyze the peptidoglycan cross-links continue to function, even while those that form such cross-links do not. This weakens the cell wall of the bacterium, and osmotic pressure continues to rise—eventually causing cell death (cytolysis). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the cell wall's peptidoglycans. The small size of the penicillins increases their potency, by allowing them to penetrate the entire depth of the cell wall. This is in contrast to the glycopeptide antibiotics vancomycin and teicoplanin, which are both much larger than the penicillins.Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with penicillin.Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms.Penicillins, like other β-lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports the endosymbiotic theory of the evolution of plastid division in land plants.Two major drawbacks of Penicillin is anaphyletic reaction( hypersensitivity) & evolution of Penicillin resistance in bacteria. Such resistant bacteria produce Penicillinase(B-lactamase) that convert penicillin to harmless Penicilloic acid. Eg Penicillinase producing N. gonorrhoeae .Development from Penicillins:
The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin (bioavailability, spectrum, stability, tolerance).The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, dicloxacillin, and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the methicillin-resistant Staphylococcus aureus (MRSA) strains that subsequently emerged.Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinam, the carbapenems and, most important, the cephalosporins, still retain it at the center of their structures.Recently, many semisynthetic penicillins have been produced like Ampicillin, Amoxycillin, Methicillin, Oxacillin, Clavulanic acid, Carbenicillin.
Inhibition of cell wall synthesis--is this the mechanism of action of penicillins?Abstract:
Penicillins have been shown to inhibit bacterial cell wall synthesis, and interact with penicillin binding proteins, leading to bacterial lysis. These two mechanisms, the former more than the latter are believed to be responsible for their therapeutic potential. It has further been demonstrated that only actively multiplying cells are susceptible to bactericidal effects of the antibiotic, which is in accordance with the suggested mechanism of action. Bacterial growth takes place in terms of size and number, both requiring additional cell wall. An increase in bacterial size is due to an increase in the volume of cytosol and area of the cell wall. Presently there is no proof that the former is the cause of the latter or vice versa. Penicillin by inhibiting cell wall synthesis would inhibit both growth and multiplication. Since the antibiotic is bactericidal to rapidly multiplying cells, its effect on cell wall would interfere with its bactericidal action. As per the present understanding penicillin acts principally by inhibiting cell wall synthesis. There is however a discrepancy between its observed effects and what should logically be expected, which forces us to reexamine the mechanism of action of penicillin. We believe that the present understanding of the action of penicillin is incomplete if not outright faulty. It would be expedient to radically modify the same in view of its implication, for example on drug development.Please visit the following links: