Antibiotic types and mechanism of action
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This document discusses various classes of antimicrobial agents including antibiotics, antifungals, and antivirals. It describes the discovery and mechanisms of several important antibiotics such as penicillin, cephalosporins, tetracyclines, aminoglycosides, and sulfonamides. It explains how these antibiotics inhibit bacterial cell wall synthesis, protein synthesis, or nucleic acid synthesis. The document also summarizes antifungal drugs such as imidazoles, nystatin, and griseofulvin and how they disrupt fungal membrane permeability or inhibit sterol synthesis. Finally, it briefly mentions antiviral drugs such as acyclovir and AZT that interfere with viral DNA or RNA synthesis.
Antibiotic types and mechanism of action
- 1. Dr. Harinatha Reddy M.sc, Ph.D. biohari14@gmail.com Department of Microbiology Sri Krishnadevaraya University Anantapur, A.p. India
- 2. Modern medicine is dependent on chemotherapeutic agents and Antibiotics that are used to treat disease. Antibiotics destroy pathogenic microorganisms or inhibit their growth at low concentrations without damage to the host. Most of the antibiotics microbial products or their derivatives that can kill microorganisms or inhibit their growth. Drugs such as the sulfonamides are sometimes called antibiotics although they are chemotherapeutic agents, not microbially synthesized.
- 3. The Development of Chemotherapy The modern era of chemotherapy began with the work of the German physician Paul Ehrlich (1854–1915). By 1904 Ehrlich found that the dye trypan red was active against the Trypanosoma that causes African sleeping sickness. He also found that compound Salvarsan 606, (arsphenamine), was active against the syphilis. Gerhard Domagk had actually discovered sulfonamides or sulfa drugs and for this discovery he received the Nobel Prize in 1939.
- 4. Although penicillin was actually discovered in 1896 by a 21-year- old French medical student named Ernest Duchesne, his work was forgotten, and penicillin was rediscovered (1928) and brought to the attention of scientists by the Scottish physician Alexander Fleming. Selman Waksman announced in 1944 that he had found a new antibiotic, Streptomycin, produced by the Streptomyces griseus. Waksman received the Nobel Prize in 1952, and his success led to a worldwide search for other antibiotic-producing soil microorganisms. Microorganisms producing chloramphenicol, neomycin, tetramycin, and tetracycline were isolated in1953.
- 5. Static or cidal Chemotherapeutic agents, can be either cidal or static. Static agents reversibly inhibit growth; if the agent is removed, the microorganisms will recover and grow again. Although a cidal agent kills the target pathogen, its activity is concentration dependent and the agent may be only static at low levels.
- 8. Chemotherapeutic agent against a pathogen can be obtained from the minimal inhibitory concentration (MIC). The MIC is the lowest concentration of a drug that prevents growth of a particular pathogen. The minimal lethal concentration (MLC) is the lowest drug concentration that kills the pathogen.
- 12. Antibacterial Drugs Penicillin G (benzylpenicillin), the first antibiotic to be widely used in medicine. Most penicillins are derivatives of 6-aminopenicillanic acid and differ from one another only with respect to the side chain attached to its amino group. The most crucial feature of the molecule is the (All penicillins are β-lactam antibiotics) β -lactam ring, which appears to be essential for activity. Penicillinase, the enzyme synthesized by many penicillin- resistant bacteria, destroys penicillin activity by hydrolyzing a bond in this ring.
- 13. The mechanism of action of penicillins is still not completely known. Their structures penicillins resemble that of the terminal D- alanyl-D-alanine found on the peptide side chain of the peptidoglycan subunit. Penicillins exert their effect by competitively inactivating the serine molecules at catalytic site of transpeptidase also known as PBPs. It has been proposed that penicillins inhibit the enzyme catalyzing the transpeptidation reaction, which would block the synthesis of a complete, fully cross-linked peptidoglycan and lead to osmotic lysis.
- 14. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by penicillin-binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of NAM (peptidoglycan precursors) to crosslink the peptidoglycan. Beta-lactam antibiotics mimic the D-Ala-D-Ala site, thereby irreversibly inhibiting PBP crosslinking of peptidoglycan.
- 16. The mechanism is consistent with the observation that penicillins act only on growing bacteria that are synthesizing new peptidoglycan. Penicillin may stimulate special proteins called bacterial holins to form holes in the plasma membrane. This would directly lead to membrane leakage and death. About 10% of people report that they are allergic to penicillin; however, up to 90% of this group may not actually be allergic.
- 17. Penicillins differ from each other in several ways. Penicillin G is effective against gonococci, meningococci, and several gram positive pathogens such as streptococci and staphylococci but it must be administered intravenous because it is destroyed by stomach acid. Penicillin V (Phenoxymethyl penicillin) is similar to penicillin G, but it is more acid resistant and can be given orally.
- 18. Ampicillin: can be administered orally and has a broader spectrum of activity as it is effective against gram-negative and positive bacteria such as Haemophilus, Salmonella, and Shigella. An increasing number of bacteria are penicillin resistant. Penicillinase-resistant penicillins such as methicillin, nafcillin, and oxacillin are frequently employed against these bacterial pathogens.
- 20. Beta-lactamases also known as penicillinase produced by bacteria, that provide multi-resistance to β-lactam antibiotics . Through hydrolysis, the lactamase enzyme breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.
- 21. Cephalosporins: Cephalosporins are a family of antibiotics originally isolated in 1948 from the fungus Cephalosporium, and their -lactam structure is very similar to that of the penicillins. Cephalosporins resemble penicillins in inhibiting the transpeptidation reaction during peptidoglycan synthesis. Cephalosporins is resistant to destruction by β-lactamases and effective against many gram-negative and positive bacteria, including Pseudomonas aeruginosa.
- 22. Most cephalosporins (including cephalothin, cefoxitin, and ceftriaxone) are administered intramuscular.
- 25. Ampicillin: Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections and meningitis. Ampicillin is in the penicillin group of beta-lactam antibiotics It is roughly equivalent to amoxicillin in terms of activity. Ampicillin is able to penetrate Gram-positive and some Gram- negative bacteria. It differs from penicillin G, only by the presence of an amino group. That amino group helps the drug penetrate the outer membrane of Gram-negative bacteria.
- 26. Ampicillin acts as an irreversible inhibitor of the enzyme transpeptidase, which is needed by bacteria to make the cell wall. It inhibits the third and final stage of bacterial cell wall synthesis in binary fission, which ultimately leads to cell lysis; therefore, ampicillin is usually bacteriolytic.
- 27. Methicillin: Methicillin also known as Meticillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. Like other beta-lactam antibiotics, meticillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of gram-positive bacteria. It does this by binding to and competitively inhibiting the transpeptidase enzyme (also known as penicillin-binding proteins (PBPs)). Meticillin was used to treat infections caused by certain gram-positive bacteria including Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pneumoniae. Meticillin is no longer effective against these organisms due to resistance.
- 28. Tetracyclines: The tetracyclines are a family of antibiotics with a common four-ring structure to which a variety of side chains are attached. These antibiotics inhibit protein synthesis by combining with the small (30S) subunit of the ribosome and inhibiting the binding of aminoacyl-tRNA molecules to the ribosomal A site. Tetracyclines are broad-spectrum antibiotics active against gram-negative bacteria, gram-positive bacteria, chlamydiae, and mycoplasmas.
- 29. High doses may result in nausea, diarrhea, yellowing of teeth in children, and damage to the liver and kidneys. Oxytetracycline and chlortetracycline are naturally produced by some species of the Streptomyces.
- 30. Erythromycin: Erythromycin, is the most frequently used antibiotic, is synthesized by Streptomyces erythraeus. Erythromycin is usually bacteriostatic and binds with the 23S rRNA of the 50S ribosomal subunit to inhibit peptide chain elongation during protein synthesis. Erythromycin is a relatively broad-spectrum antibiotic effective against gram-positive bacteria, mycoplasmas, and a few gram- negative bacteria.
- 31. Aminoglycoside Antibiotics: The important aminoglycoside antibiotics are Streptomycin, kanamycin, gentamicin and neomycin are synthesized by Streptomyces. Whereas gentamicin comes from a related bacterium, Micromonospora purpurea. All aminoglycosides contain a cyclohexane ring and amino sugars.
- 32. Streptomycin: Streptomycin is a protein synthesis inhibitor. It binds to the small 16S rRNA of the 30S subunit of the bacterial ribosome, interfering with the binding of formyl-methionyl- tRNA to the 30S subunit. Streptomycin was discovered in 1943 from Streptomyces griseus.
- 35. Chloramphenicol: Chloramphenicol was first produced from cultures of Streptomyces venezuelae, it is now made through chemical synthesis. Like erythromycin, chloramphenicol binds to 23S rRNA on the 50S ribosomal subunit. It inhibits the peptidyl transferase and is bacteriostatic.
- 36. Quinolones: The quinolones are synthetic drugs that contain the 4- quinoline ring. The first quinolone, nalidixic acid was synthesized in 1962. More recently a family of fluoroquinolones has been produced. Three of these—ciprofloxacin, norfloxacin, and ofloxacin—are currently used in the United States.
- 37. Quinolones act by inhibiting the bacterial DNA gyrase or topoisomerase II, probably by binding to the DNA gyrase complex. This enzyme introduces negative twists in DNA and helps separate its strands. DNA gyrase inhibition disrupts DNA replication and repair, transcription, bacterial chromosome separation during division, and other cell processes involving DNA.
- 38. They are highly effective against enteric bacteria such as E. coli, Klebsiella pneumoniae, Haemophilus, Neisseria, Pseudomonas aeruginosa, and other gram-negative pathogens. The quinolones also are active against gram-positive bacteria such as Staphylococcus aureus, Streptococcus pyogenes, and Mycobacterium tuberculosis.
- 39. Rifampicin: Rifampicin, also known as rifampin, is an antibiotic used to treat several types of bacterial infections. This includes Tuberculosis, leprosy, Haemophilus influenzae type b and meningococcal diseases. Rifampicin inhibits bacterial m-RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase. Crystal structure data and biochemical data suggest that rifampicin binds to the RNA polymerase β subunit within the DNA/RNA channel. The inhibitor prevents RNA synthesis by physically blocking elongation, and thus preventing synthesis of host bacterial proteins.
- 40. Polymyxin B: Polymyxin B is an antibiotic primarily used for resistant Gram- negative infections. It is derived from the bacterium Bacillus polymyxa. It has a bactericidal action against almost all Gram-negative bacilli. Alters bacterial outer membrane permeability by binding to a negatively charged site in the lipopolysaccharide layer. which has an electrostatic attraction for the positively charged amino groups.(this site normally is a binding site for calcium and magnesium counter ions);. The result is a destabilized outer membrane and disrupts membrane integrity. Leakage of cellular molecules, inhibition of cellular respiration
- 41. Sulfonamides or Sulfa Drugs: A good way to inhibit or kill pathogens is by use of compounds that are structural analogues, molecules structurally similar to metabolic intermediates. These analogues compete with metabolites in metabolic processes because of their similarity.
- 42. When sulfanilamide or another sulfonamide enters a bacterial cell, it competes with p-aminobenzoic acid for the active site of an enzyme involved in folic acid synthesis, and the folate concentration decreases. The decline in folic acid is detrimental to the bacterium because folic acid is essential to the synthesis of purines and pyrimidines. The bases used in the construction of DNA, RNA, and other important cell constituents. The resulting inhibition of purine and pyrimidine synthesis leads to inhibition of bacterial growth or death of the pathogen.
- 43. Antifungal Drugs: Fungal infections are often subdivided into infections superficial mycoses and systemic mycoses. Several drugs are used to treat superficial mycoses. Drugs containing imidazole ring are broad-spectrum agents available as creams and solutions for the treatment of dermatophyte infections such as foot, and oral candidiasis. They are thought to disrupt fungal membrane permeability and inhibit sterol synthesis.
- 44. Nystatin a polyene antibiotic from Streptomyces, is used to control Candida infections of the skin. Like amphotericin B and natamycin binds to ergosterol, a major component of the fungal cell membrane. At high concentration, it forms pores in the membrane that lead to K+ leakage and death of the fungus. Griseofulvin an antibiotic formed by Penicillium, is given orally to treat chronic dermatophyte infections. It inhibit cell division; it also may inhibit protein and nucleic acid synthesis.
- 45. Antiviral drugs: Most antiviral drugs disrupt the synthesis of virus-specific nucleic acids. Acyclovir, is also used in the treatment of herpes infections. Upon phosphorylation, acyclovir resembles deoxy-GTP and inhibits the virus DNA polymerase. Azidothymidine (AZT) or Zidovudine, lamivudine (3TC), interfere with reverse transcriptase activity and therefore block HIV reproduction. The combination of AZT and lamivudine, is very effective in reducing HIV plasma concentrations almost to zero. However, the treatment does not seem able to eliminate latent proviral HIV DNA that still resides in memory T cells.
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