1. Antibiotics STRUCTURE, SYNTHESIS AND BIOLOGICAL EFFECTS

2. Definition and classification An antibiotics are the agent that either kills or inhibits the growth of a microorganism by biochemical process. The term antibiotic was first used in 1942 by Selman Waksman and his collaborators in journal articles to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution. Antibiotics that kill bacteria are called "bactericidal" Antibiotics that stop the growth of bacteria are called "bacteriostatic" Antibiotics are commonly classified based on their mechanism of action, chemical structure, spectrum of activity. Selman Abraham Waksman 1888 - 1973 Most antibiotics target bacterial functions or growth processes. Antibiotics that target the bacterial cell wall (penicillins, cephalosporins), or cell membrane (polymixins), or interfere with essential bacterial enzymes (quinolones, sulfonamides) are usually bactericidal in nature. Those that target protein synthesis, such as the aminoglycosides, macrolides, and tetracyclines, are usually bacteriostatic.

4. Further categorization is based on their target specificity: narrow-spectrum antibiotics target particular types of bacteria, such as Gram-negative or Gram-positive bacteria, while broad-spectrum antibiotics affect a wide range of bacteria. Gram-staining: A test, resulting in the classification of bacteria, developed in the last century by Hans Christian Gram, a Danish microbiologist: - Gram positive bacteria will retain the original blue stain - Gram negative bacteria will lose the blue stain upon intermediate acetone treatment and will stain red Gram staining differentiates bacteria by the chemical and physical properties of their cell walls by detecting peptidoglycan, which is present in a thick layer in gram-positive bacteria. In a Gram stain test, gram-positive bacteria retain the crystal violet dye, while a counterstain (commonly safranin or fuchsin) added after the crystal violet gives all gram-negative bacteria a red or pink coloring. The Gram staining is a valuable diagnostic tool in both clinical and research settings, not all bacteria can be definitively classified by this technique.

5. Classes of antibiotics β-Lactam antibiotics 1928: A. Fleming discovered that his cultures of staphylococci was contaminated with a fungus, and that the colonies of staphylococci immediately surrounding the fungus had been destroyed, whereas other staphylococci colonies farther away were normal. This fungi was the Penicillium notatum which produced a bactericidal agent. The penicillins are the oldest of the clinical antibiotics, but are still the most widely used. The first of the many penicillins to be employed on a significant scale was penicillin G (benzylpenicillin), obtained from the fungus Penicillium chrysogenum by fermentation in a medium containing corn-steep liquor. The α- aminoadipyl side-chain of isopenicillin N is removed and replaced by another acid according to its availability from the fermentation medium. Several other penicillins are accessible by supplying different acids. Alexander Fleming 1881 - 1955 Penicillium notatum

6. Synthesis of penicillins by fermentation Penicillin is a secondary metabolite of certain species of Penicillium and is produced when growth of the fungus is inhibited by stress. It is not produced during active growth. Penicillin is produced by the fungus Penicillium chrysogenum which requires lactose, other sugars, and a source of nitrogen (in this case a yeast extract) in the medium to grow well. F GXKOV

7. Semisynthesis" or partial chemical synthesis: compounds isolated from natural sources (e.g. plant material or bacterial or cell cultures) are used as starting materials. Semisynthesis is usually used when the precursor molecule is too structurally complex, too costly or too inefficient to be produced by total synthesis. It is also possible that the semisynthetic derivative outperforms the original biomolecule itself with respect to potency, stability or safety. Cloxacillin and temicillin are antibiotic useful for the treatment of a number of bacterial infections. These are semisynthetic and in the same class as penicillin. Both compounds have large R chain, which does not allow the beta-lactamases to bind. This drug has a weaker antibacterial activity than benzylpenicillin, and is devoid of serious toxicity except for allergic reactions.

8. Penicillins and other β-lactam drugs exert their antibacterial effects by binding to proteins (penicillin-binding proteins), peptidase enzymes that are involved in the late stages of the biosynthesis of the bacterial cell wall. Cross-linking of the peptidoglycan chains which constitute the bacterial cell wall involves a terminal D-Ala–D-Ala intermediate which, in its transition state conformation, closely resembles the penicillin molecule. As a result, the penicillin occupies the active site of the enzyme and becomes bound via an active- site serine residue, this binding causing irreversible enzyme inhibition and cessation of cell wall biosynthesis. Growing cells are then killed due to rupture of the cell membrane and loss of cellular contents. The bacterial cell wall has no counterpart in mammalian cells, and the action is thus very specific.

9. Antibiotic resistence Antibiotic resistance is a form of drug resistance whereby some (or, less commonly, all) sub-populations of a microorganism, usually a bacterial species, are able to survive after exposure to one or more antibiotics; pathogens resistant to multiple antibiotics are considered multidrug resistant (MDR) or, more colloquially, superbugs. Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has emerged as one of the pre- eminent public health concerns of the 21 st century, in particular as it pertains to pathogenic organisms (the term is especially relevant to organisms that cause disease in humans).

10.  -laktamase inhibitors Amoxacillin + clavulanic acid A β-lactamase inhibitor (or beta-lactamase inhibitor) is a molecule used in conjunction with a β-Lactam antibiotic to extend its spectrum of activity. Although β-lactamase inhibitors have little antibiotic activity of their own, they instead inhibit the activity of β-lactamases, a family of enzymes that break the beta-lactam ring that allows penicillin-like antibiotics to work, thereby conferring bacterial resistance.

11. Aminoglycosides The aminoglycosides form an important group of antibiotic agents and are immediately recognizable as modified carbohydrate molecules. Typically, they have two or three uncommon sugars, mainly aminosugars, attached through glycoside linkages to an aminocyclitol, i.e. an amino-substituted cyclohexane system, which also has carbohydrate origins. The aminoglycoside antibiotics have a wide spectrum of activity, includingactivity against some Gram-positive and many Gram- negative bacteria. They must be administered by injection. The widespread use of aminoglycoside antibiotics is limited by their nephrotoxicity, which results in impaired kidney function, and by their ototoxicity, which is a serious side-effect and can lead to irreversible loss of hearing. The aminoglycoside antibiotics interfere with protein biosynthesis.

12. Cyclic peptide antibiotics The cyclosporins are a group of cyclic peptides produced by fungi such as Cylindrocarpon lucidum and Tolypocladium inflatum. These agents show a narrow range of antifungal activity, but high levels of immunosuppressive and anti- inflammatory activities. It is now widely exploited in organ and tissue transplant surgery to prevent rejection following bone-marrow, kidney, liver, pancreas, lung, and heart transplants. It has revolutionized organ transplant surgery, substantially increasing survival rates in transplant patients. Cyclosporin A Glycopeptide antibiotics Bleomycin is a mixture of glycopeptide antibiotics isolated from cultures of Streptomyces verticillus, and used for its anticancer activity. Bleomycin is a DNA-cleaving drug, causing single and double strand breaks in DNA. Vancomycin is frequently the last-resort agent in the control of methicillinresistant Staphylococcus aureus (MRSA), since many strains have become resistant to all other antibiotics. It has activity against Gram-positive bacteria, especially resistant strains of staphylococci, streptococci, and enterococci. Bleomycin

13. Vancomycin

14. Macrocyclic lactone antibiotics The macrolide antibiotics are macrocyclic lactones with a ring size typically 12–16 atoms, and with extensive branching through methyl substituents. Polyene macrolides are larger in the range 26–38 atoms. The largest natural macrolide structure discovered has a 66-membered ring. Two or more sugar units are attached through glycoside linkages; these sugars tend to be unusual 6-deoxy structures often restricted to this class of compounds. Macrolides are protein synthesis inhibitors. eritromicin Erythromycin activity is predominantly against Gram- positive bacteria, and the antibiotic is prescribed for penicillinallergic patients Most polyene macrolides have antifungal properties, but not antibacterial activity. The macrolide ring size ranges from 26 to 38 atoms, and this also accommodates a conjugated polyene of up to seven E double bonds. Amphotericin is active against most fungi and yeasts, but it is not absorbed from the gut, so oral administration is restricted to the treatment of intestinal candidiasis. It is administered intravenously for treating potentially life- threatening systemic fungal infections. Polyene macrolides

15. The tetracyclines are a group of broad-spectrum, orally active antibiotics produced by species of Streptomyces, and several natural and semisynthetic members are used clinically. Their antimicrobial activity arises by inhibition of protein synthesis. Although the tetracycline antibiotics have a broad spectrum of activity spanning Gram-negative and Gram- positive bacteria, their value has decreased as bacterial resistance has developed in pathogens such as Pneumococcus, Staphylococcus, Streptococcus, and E. coli. Tetracycline antibiotics chlortetracycline Antracycline antibiotics A number of anthracycline antibiotics, e.g. doxorubicin (one of the most successful and widely used antitumour drugs) from Streptomyces peuceticus and daunorubicin from Streptomyces coeruleorubicus, have structurally similar tetracyclic skeletons and would appear to be related to the tetracyclines. However, anthraquinone derivatives are intermediates in anthracycline biosynthesis, and the fourth ring is constructed later. doxorubicin