Antibiotics and Antimicrobial Agents

Antibiotics and Antimicrobial Agents Antibiotics are microbial metabolites or synthetic analogs inspired by them that, in small doses, inhibit the growth and survival of microorganisms without serious toxicity to the host. Selective toxicity is the key concept. Examples are the penicillins and the tetracyclines. The first truly effective antimicrobial agents date from the mid 1930s (the sulfonamides) and the first antibiotics came into use in the 1910s (the penicillins) In main cases the clinical utility of natural antibi­otics has been enhanced through medicinal chemical ma­nipulation of the original structure leading to broader an­timicrobial spectrum, greater potency, lesser toxicity, more' convenient administration, etc. Examples of such semisynthetic antibiotics are amoxicillin and doxycycline.

General principles Drug Nomenclature The penicillins are produced by fermentation of fungi and their names most commonly end in the suffix -cillin as ampicillin. The cephalosporins are fungal products their names mostly begin with the prefix cef- or ceph- The synthetic fluoroquinolones mostly end in the suffix -floxacin. Antibiotics produced by fermentation of various Streptomyces species, by convention have names ending with the suffix –mycin e.g. streptomycin. Antibiotics produced by fermentation of various Micromonospora sp. have names ending in -micin e.g. Gentamicin.

General principles Broad spectrum antibiotics: they have the potential of inhibiting a wide range of bacter­ial genera belonging to both Gram (+) and Gram (-) cultures Narrow-spectrum antibiotics: they inhibit only a few bacterial genera such as the glycopeptides, typified by vancomycin, which are used for a few Gram (+) and anaerobic microorganisms. Bactericidal antibiotics: they will kill bacteria, if the concentration or the dose is very high. Bacterostatic antibiotic, will interrupt the growth of the bacteria and up on withdrawal the growth the organism can resume the growth and the infection can reestablish it self because it is still alive.

General principles The spread between the bactericidal dose and the bacteriostatic dose is characteristic of a given families e.g.: With gentamicin, doubling the dose changes the effect on bacteria from bactericidal to bacteriostatic. With tetracycline, the difference between the bacteriostatic and the bactericidal dose is 40 fold.

Therapeutic classes Synthetic antimicrobial agents

Synthetic antimicrobial agents Synthetic antimicrobial agents have not been modeled after any natural product so they may not properly be called "antibiotics." Some synthetics are extremely effective for treatment of infections and are widely used. They are all effective against key enzymes needed for the biosynthesis of nucleic acids. Because they interrupt the biosynthesis of nucleic acids rather than attacking the finished products or substituting for them in nucleic acids they are not genotoxic but are comparatively safe to use.

Sulfonamides

A- Sulfonamides Sulfonamides were discovered in the mid 1930s following examination of the Prontosoil rubrum dye. It was found that; the active substance is p-aminobenzenesulfonic acid amide (sulfanilamid), formed by reductive liver metabolism of the administered dye i.e. prontosil rubrum is a pro-drug.

Mechanism of Action Sulfonamides are bacteriosiatic, they inhibit the enzyme dihydropteroate synthase needed for the biosynthesis of folic acid derivatives and. ultimately, DNA, How? They do this by competing at the active site with p-aminobenzoic acid (PABA) which incorporated into the developing tetrahydrofolic acid molecule by condensation with a dihydropteroate diphosphate precursor under the influence of dihydropteroate synthetase.

Mechanism of Action

Mechanism of Action Thus sulfonamides may be classified as antimetabolites Most susceptible bacteria are unable to take up preformed folic acid from their environment and convert it to a tetrahydrofolic acid but, instead, synthesize their own folates de novo. As folates are essential intermediates for the preparation of certain DNA bases, without which bacteria cannot multiply, this inhibition is strongly bacteriostatic. Humans are unable to synthesize folates from component parts, lacking the necessary enzymes (including dihydropteroale synthase), and folic acid is consumed as a dietary so sulfonamides have no lethal effect upon human cell growth.

Mechanism of Action In a few strains of bacteria, sulfonamides are attached to the dihydropteroate diphosphate in the place of the normal PABA giving false metabolite which is not capable of undergoing condensation with glutamic acid and inhibit the enzyme and the net result is inability of the bacteria to multiply as soon as the preformed folic acid in their cells is used up and further nucleic acid biosynthesis becomes impossible. Bacteria which are able to take up pre­formed folic acid into their cells are resistant to sulfonamides.

Structure-activity Relationships The strongly electron withdrawing character of the aromaticSO2 group makes the nitrogen atom to which it is directly attached partially electropositive, thus increasing the acidity of the hydrogen atoms attached to the nitrogen so that this functional group is slightly acidic Replacement of one of the NH2 hydrogen by an electron withdrawing heteroaromatic ring was not only consistent with antimicrobial activity but also greatly acidified the remaining hydrogen and dramatically enhanced potency and dramatically increases the water solubility under physiologic conditions. The poor water solubility of the earliest sulfonamides led to occasional crystallization in the urine (crystalluria) and resulted in kidney damage because the molecules were unionized at urine pH values.

Structure-activity Relationships

Therapeutic Applications Sulfisoxazole and its pro-drug acetyl sulfisoxazole Its clinical use is restricted to the treatment of the primary uncomplicated urinary tract infections. Sulfisoxazole is well absorbed following oral administra­tion distributes widely and is excreted by the kidneys.

Therapeutic Applications Sulfonamides are deactivated by acetylation at N-4 and glucuronation of the aniline nitrogen in the liver. Allergic reactions are the most common and take the form of rash, photosensitivity and drug fever. The most severe side effect is the Stevens-Johnson syndrome characterized by sometimes-fatal erythrema multiforme and ulceration of mucous membranes of the eye, mouth and urethra.

Therapeutic Applications Other sulfonamides still in use include sulfadiazine, sulfamethizole and sulfamethoxazole.

Therapeutic Applications Multiple (or triple) sulfas are a 1:1:1 combination of sulfabenzamide, sulfacetamide and sulfathiazole which used as a cream for carderella vaginalis vaginal infection

Therapeutic Applications Sulfasalazine is a pro-drug given orally and is largely not absorbed in the gut so the majority of the dose is delivered to the distal bowel where reductive metabolism by gut bacteria converts the drug to sulphapyridine and 5-aminosaliclic acid (Mesalamine).

Therapeutic Applications The liberation mesalamine, an anti-inflammatory agent, is the purpose for administering this drug. This agent is used to treat ulcerative colitis and Crohns disease. Direct ad­ministration of salicylates is otherwise irritating to the gastric mucosa.

Trimethoprim

Mechanism of Action Trimethoprim inhibits the dihydrofolate reductase required for reduction of the exogenous folic acid stepwise to dihydrofolic acid and then to tetrahydrofolic acid an important cofactor essential for purine biosynthesis and ultimately for DNA synthesis. Endogenous produced dihydrofolate must also reduced by the same enzyme to enter the pathway involved in DNA synthesis. The bacterial enzyme and the mammalian enzyme both efficiently catalyze the conver­sion of dihydrofolic acid to tetrahydrofolic acid, but the bacterial enzyme is sensitive to inhibition by trimethoprim by up to 40,000 times lower concentrations than is the mammalian enzyme. This difference explains the useful selective toxicity of trimethoprim

Mechanism of Action

Therapeutic Application Trimethoprim is used as a single agent for the oral treatment of uncomplicated urinary tract infections caused by susceptible bacteria Most commonly used in 1:5 fixed ratio with the sulfamethoxazole (Bactrim, Septra). This combination is not only synergistic but is less likely to induce bacterial resistance than either agent alone. These agents block sequentially at two different steps in the same essential pathway, and this combination is extremely difficult for a naive microorganism to survive. Combined with sulfamethoxazole, it is used for oral treatment of urinary tract infections, shigellosis, otitis media, traveler's diarrhea, and bronchitis. The most frequent side effects of are rush, nausea and vomiting.