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Classes of antimicrobial agents

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Dr. Geoffrey K. K. Maiyoh, profile picture
Dr. Geoffrey K. K. Maiyoh

The document discusses various classes of antimicrobial agents that act by inhibiting bacterial cell wall synthesis. It begins by describing the different types of bacterial cell walls and then focuses on antibiotics that target cell wall synthesis. Specifically, it covers beta-lactam antibiotics such as penicillins and cephalosporins, which inhibit the final step of peptidoglycan synthesis. It describes the classification, mechanisms of action, and examples within each class. Carbapenems and monobactams, which also inhibit cell wall synthesis, are also discussed.

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MBSM 713: BIOCHEMISTRY OF ANTI MICROBIAL AGENTS Lecture Two: Survey of major antimicrobial drug groups 1.ANTIBACTERIAL AGENTS (Antibiotics) Dr. G. Kattam Maiyoh 01/23/15 1 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Classification: Mode of action 01/23/15 2 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Inhibitors of Cell Wall Synthesis 01/23/15 3 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
01/23/15 4 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 Bacterial cell wall • There are three types – Gram-positive (e.g. Staphylococci, Listeria • Have many peptidoglycan layers • stains with crystal violet • typically lack the outer membrane found in gram-ve. – Gram-negative (e.g. E.coli, Salmonella) • Have few peptidoglycan layers • (stain safranin or fuchsin) – Acid-fast Positive (Mycobacteria) • Cell wall contains waxy substance (Mycollic acid) • Stains with acid fast (heating required)
Antibiotics - Cell wall synthesis inhibitors Beta-lactam antibiotics: 1928 - Alexander Fleming observes the antibacterial effects of Penicillin 1940 - Florey and Chain extract Penicillin 01/23/15 5 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
The beta lactams • The β-lactam group of antibiotics includes an enormous diversity of natural and semi-synthetic compounds that inhibit several enzymes associated with the final step of peptidoglycan synthesis. • All of this enormous family are derived from a β -lactam structure: a four-membered ring in which the β -lactam bond resembles a peptide bond. • The multitude of chemical 01/23/15 6 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
The Beta-Lactams 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 7 R – variable side chain Monobactam nucleus
Penicillinase (β Lactamase) - Represents a great challenge to the action of the beta lactams Figure 20.8 More when we discuss antibiotic resistance 01/23/15 8 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
• Penicillium notatum produces the only naturally occurring agent – penicillin G or benzylpenicillin • Penicillium chrysogenum produces 6-aminopenicillanic acid, raw material for semi-synthetics penicillins 01/23/15 9 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Targets for beta lactams 1. The targets for β-lactam drugs are the penicillin binding proteins (PBP's), so called because they bind radioactive penicillin and can be detected by autoradiography of gels on which bacterial proteins have been separated electrophoretically. • The penicillin binding proteins have transpeptidase or carboxypeptidase activity and they act to regulate cell size and shape. • They are also involved in septum formation and cell division. Bacteria have several individual penicillin binding proteins, each with a separate function. • Conventionally these are numbered according to size, with PBP 1 as the largest protein. • The PBP 1 of one bacterium will not necessarily have the same function as the PBP 1 of a different organism. 01/23/15 10 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Target 2. The β-lactam antibiotics also stimulate the activity of autolysins by inactivating an inhibitor => lysis • Autolysins are enzymes that are responsible for the natural turnover of cell wall polymers to permit growth of the cells. • Under normal conditions, these enzymes produce controlled weak points within the peptidoglycan structure to allow for expansion of the cell wall structure. • This activity is stimulated by β-lactams, causing a breakdown of peptidoglycan and leading to osmotic fragility of the cell and ultimately to cell lysis. 01/23/15 11 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Penicillins - classification – Narrow spectrum – penicillinase sensitive – Narrow spectrum – penicillinase resistant – Broad spectrum penicillins – Extended-spectrum penicillins • Cephalosporines • Carbapenems • Monobactams • Vancomycin, Bacitracin 01/23/15 12 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Penicllins (pharmacokinetics) • Attains therapeutic concentration in most tissues • However has poor CSF penetration • Renal excretion (Excretion) • Side effects: hypersensitivity, nephritis, neruotoxicity, platelet dysfunction 01/23/15 14 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Narrow spectrum – penicillinase (= β-lactamase) sensitive • Benzylpenicillin – Naturally occuring – Poor oral availability (sensitive to stomach acid) => given by injection – Active against gram-positive bacteria • Phenoxymethylpenicillin – Better oral availability (acid resistant) 01/23/15 15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Narrow spectrum – penicillinase (= β-lactamase) resistant • Methicillin – Semisynthetic – Poor oral availability (only parenteral) – Active against gram-pos bacteria – Mostly used for Staphylococcus aureus • Oxacillin – Good oral availability • Cloxacillin • Dicloxacillin 01/23/15 16 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Broad spectrum – penicillinase (β- lactamase) sensitive (Also referred to as Aminopenicillins) • Ampicillin – Semisynthetic – Good oral availability – Active against gram-pos and gram-neg bacteria – Active against enterobacteria e.g. kleb. Shig. Salm • Amoxicillin – Excellent oral availability 01/23/15 17 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Extended spectrum – penicillinase (β- lactamase) sensitive (Also called Carboxypenicillins) • Carbenicillin – Semisynthetic – Poor oral availability – Active against gram-pos and gram-neg bacteria – Active against Pseudomonas aeruginosa and Klebsiella • Ticarcillin • Mezlocillin • Pipercillin 01/23/15 18 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Penicillins Figure 20.6 01/23/15 19 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 20
Cephalosporins • Share the same antibiotic mechanism as penicillins • Cross-allergies with penicillins are common • Some CSs antagonize Vitamin K => leads to bleeding • Some CSs block alcohol oxidation => disulfiram effect (allergic reactions, seizures, extreme tiredness and dark urine) Classified into generations: 1- 4  • Increasing activity against gram-negative bacteria and anaerobes • Increasing resistance to destruction by beta-lactamases • Increasing ability to reach cerebrospinal fluid 01/23/15 21 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Cephalosporins • The first to be discoverded were called first generation while later, more extended spectrum cephalosporins were classified as second, third and 4th generation cephalosporins in this order. • Each newer generation has significantly greater gram- negative antimicrobial properties than the preceding generation, • Most cases with decreased activity against gram- positive organisms. • Fourth generation cephalosporins, however, have true broad spectrum activity. 01/23/15 22 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
01/23/15 23 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 24 Cephalosporin structure
• Base molecule is 7- aminocephalosporanic acid produced by a Sardinian sewer mold • R groups determine spectrum of activity and pharmacological properties • Mechanism of action/resistance and class pharmacology is essentially the same as penicillins 01/23/15 25 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
First Generation Cephalosporins • Cefazolin, cephalexin, cephadroxil • Excellent against susceptible staph and strep • Modest activity against G -ve • Cefazolin given parentally, others orally • More than half of the drug is bound to plasma proteins • Excreted by kidneys unmetabolized • Good for staph and strep skin and soft tissue infections 01/23/15 26 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Second Generation Cephalosporins • Include; – Cefaclor, – cefuroxime, – cefprozil • Modest activity against G+, increased activity against G-, works against anaerobes • Cefaclor and cefprozil given orally • Absorption and excretion same as first generation. • Good for treating respiratory tract infections, intra-abdominal infections, pelvic inflammatory disease, diabetic foot ulcers 01/23/15 27 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Third Generation Cephalosporins • Ceftaxime, ceftriaxzone, cefoperazone, cefpodoxime • Broad spectrum killers • Drugs of choice for serious infections • No effect against Listeria and beta- lactamase producing pneumococci • Cefpodoxime given orally, others parentally • Most excreted by kidney • Therapeutic uses – Bacterial meningitis – Lyme disease – Life-threatening G -ve sepsis (infection) 01/23/15 28 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Fourth Generation Cephalosporin – e.g.Cefepime –Have true broad spectrum activity ( and more beta-lactamases resistanc (effective against Gm+ and Gm-) –Given parentally, excellent penetration into CSF –Good for nosocomial infections 01/23/15 29 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 30
Toxicity/Contraindications of Cephalosporins • Hypersensitivity reactions (uncommon) essentially same as for penicillins • Cross-reaction between 2 classes 01/23/15 31 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Inhibitors of Cell Wall Synthesis 01/23/15 33GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Carbapenems • Beta-lactam ring is fused to a 5 member ring system • Effect on microbes and pharmacology of carbapenems similar to penicillins 01/23/15 34GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Selected Carbapenems • Imipenem – Broad spectrum including anaerobes and Pseudomonas aeruginosa – Parentally administered – Must be combined with cilastatin to be absorbed – Excreted by kidneys • Meropenem, ertapenem, and doripenem are similar to imipenem but don’t need co- administration with cilastatin cilastatin chemical compound which inhibits the human enzyme dehydropeptidase 01/23/15 35GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Toxicity/Contraindications of Carbapenems • Nausea and vomiting (common) • Hypersensitivity reactions (uncommon) – Essentially the same as for penicillins – Cross-reactivity is possible 01/23/15 36 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Aztrenam – a monobactam • Monobactam - beta-lactam compounds wherein the beta-lactam ring is alone and not fused to another ring • Works only on Gm -ve, including Pseudomonas aeruginosa • Useful for treating G-ve infections that require a beta-lactam because it does not elicit hypersensitivity reactions 01/23/15 37GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Beta-lactamase inhibitors a. Clavulanic acid – Irreversible inhibitor of β-lactamase – Good oral absorption – Combined with amoxicillin or ticarcillin b. Sulbactam 01/23/15 38GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Peptide Antibiotics Peptide antibiotics are drugs with polypeptides structure Sub-group of Peptide Antibiotics Polymyxins e.g. »Polymyxin B »Colistin Glycopeptides e.g. »Vancomycin »Teicoplanin »Avoparcin Bacitracin Streptogramins Each drug group has its own mechanism of action 4 groups and 4 mechanism 01/23/15 39 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
PolymyxinsPolymyxins Drug members Polymyxin B Colistin (Polymyxin E) Mechanism of action Detergent-like action Damage to cell membrane function Bind to Lipopolysaccharides (LPS) and destroy outer membrane of Gram- negative bacteria Bactericidal Concentration-dependent Non-selective on bacterial membrane Spectrum of activity Gram-negative bacteria01/23/15 40 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
PolymyxinsPolymyxins • Pharmacokinetics –Not absorbed via GI tract –If injection, drug accumulated and slowly excreted • Toxicities –Highly toxic if systemic injection –Nephrotoxic –Neurotoxic • Clinical uses –Oral treatment – 01/23/15 41 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
GlycopeptidesGlycopeptides • Group members –Vancomycin • Antibacterial activity –Inhibition of cell wall synthesis –Active against Gram-positive bacteria • Not absorbed orally, must administered IV • High toxicity –Local irritation , ototoxicity, nephrotoxicity • Clinical uses –Hardly used in animals01/23/15 42 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
BacitracinBacitracin • Drug activity –Inhibit cell wall synthesis –Activity on Gram-positive bacteria –Bactericidal • Nephrotoxic if systemic injection • Clinical uses – the same as polymyxin –Oral – as growth promoter –Local or topical drugs 01/23/15 43 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Antibiotics that Inhibit Protein Synthesis 01/23/15 44 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Protein synthesis inhibitors – Aminoglycosides – Tetracyclins - Spectinomycin – Macrolides – Chloramphenicol – Clindamycin 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 45
Inhibition of Protein Synthesis by Antibiotics Figure 20.4 01/23/15 46 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Review of Initiation of Protein Synthesis 30S 1 3 2 GTP 1 2 3 GTP Initiation Factors mRNA 3 1 2 GTP 30S Initiation Complex f-met-tRNA Spectinomycin Aminoglycosides 1 2 GDP + Pi 50S 70S Initiation Complex AP 01/23/15 47 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Review of Elongation of Protein Synthesis GTP AP Tu GTP Tu GDP Ts Ts Tu + GDP Ts Pi P ATetracycline AP Erythromycin Fusidic Acid Chloramphenicol G GTP G GDP + Pi G GDP AP + GTP 01/23/15 48 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Antimicrobials that Bind to the 30S Ribosomal Subunit 01/23/15 49 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
a) Aminoglycosides (bactericidal) streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) • Mode of action - The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur. • They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. – By binding to the 16 S r-RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity. • May also destabilize bacterial membranes. 01/23/15 50 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Microbe Library American Society for Microbiology www.microbelibrary.org 01/23/15 51 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
b) Aminoglycosides (bactericidal) streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) • Spectrum of Activity –Effective against many gram- negative and some gram-positive bacteria; • Not useful for anaerobic (oxygen required for uptake of antibiotic) or intracellular bacteria. • Resistance - Common • Synergy - The aminoglycosides synergize with β -lactam antibiotics. The β -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides. 01/23/15 52GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
c) Tetracyclines (bacteriostatic) tetracycline, minocycline and doxycycline • Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome. • Spectrum of activity - Broad spectrum; Useful against intracellular bacteria • Resistance - Common • Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth. 01/23/15 53 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
d) Spectinomycin (bacteriostatic) • Mode of action - Spectinomycin reversibly interferes with m-RNA interaction with the 30S ribosome. It is structurally similar to the aminoglycosides but does not cause misreading of mRNA. • Spectrum of activity - Used in the treatment of penicillin-resistant Neisseria gonorrhoeae • Resistance - Rare in Neisseria gonorrhoeae 01/23/15 54 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Antimicrobials that Bind to the 50S Ribosomal Subunit 01/23/15 55 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
a) Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic) • Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. • Spectrum of activity - Chloramphenicol - Broad range; Lincomycin and clindamycin - Restricted range • Resistance - Common • Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis. 01/23/15 56 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
b) Macrolides (bacteriostatic) erythromycin, clarithromycin, azithromycin, spiramycin • Mode of action - The macrolides inhibit translocation. • Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella • Resistance - Common 01/23/15 57 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Macrolides : ClassificationMacrolides : Classification • Macrolides are drugs with lactone ring structure • Sub-groups are based on no. of ring atom – 12-membered ring macrolides – 13-membered – 14-membered (many drugs) – 15-membered – 16-membered (many drugs) • Special groups – Azalides – name for 15-membered – Triamilides – name for tulathromycin (combination of 13- and 15-membered) – Ketolides – name for 14-membered with 3 keto group 01/23/15 58 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
MacrolidesMacrolides Drug examples 13-membered Tulathromycin (Triamilides) 14-membered Erythromycin Clarithromycin, Roxithromycin, Dirithromycin 15-membered Azithromycin (Azalides) Tulathromycin (Triamilides) 16-membered Spiramycin Tylosin 01/23/15 59 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Macrolides – generalMacrolides – general propertiesproperties • Mechanism of action – Inhibit protein synthesis – Bind to 50S ribosomal unit – Bacteriostatic • Spectrum of activity – Gram-positive – Some Gram- negative 01/23/15 60 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
MacrolidesMacrolides Pharmacokinetics Broad distribution in body tissues High intracellular concentration 01/23/15 61 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
MacrolidesMacrolides Additional properties of Macrolides • Anti-inflammatory effect – Inhibitory effect on neutrophils – inhibit proinflammatory cytokines – Useful for treatment of inflammatory01/23/15 62 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
ErythromycinErythromycin • Erythromycin is a standard or basic drug of macrolides • Other drug members are usually compared with erythromycin • Important adverse effect - severe diarrhea – Especially in adult horse and ruminants • Clinical uses – Second choice (alternative drug) in humans – Small animals – Fowls 01/23/15 63 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Tylosin andTylosin and SpiramycinSpiramycin • Tylosin and Spiramycin – Activities are similar to erythromycin – Good activity on Mycoplasma • Examples of Clinical uses – Whooping couph – Pneumonia – VDs – Used in ruminants01/23/15 64 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Advanced generationAdvanced generation MacrolidesMacrolides Example drugs Roxithromycin Dirithromycin Clarithromycin Azithromycin General activity – the same as erythromycin Better Pharmacokinetic properties Acid stable Fewer GI side effect Higher oral availability Longer serum half-lives Higher tissue concentrations 01/23/15 65 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
KetolidesKetolides • Ketolides are 14- membered ring macrolides with 3 keto group • Specific drugs – Telithromycin – Cethromycin (still in clinical study) • Important properties – Less resistance – Good activities on01/23/15 66 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Fusidic acid (bacteriostatic) • Selectivity due to differences in prokaryotic and eukaryotic elongation factors • Mode of action - Fusidic acid binds to elongation factor G (EF-G) and inhibits release of EF-G from the EF-G/GDP complex. • Spectrum of activity - Gram-positive cocci 01/23/15 67GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 Antimicrobials that Interfere with Elongation Factors
Inhibitors of Nucleic Acid Synthesis ~Inhibitors of DNA synthesis ~Inhibitors of RNA synthesis 01/23/15 69 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Inhibitors of RNA Synthesis For this class of antibiotics, selectivity is due to differences between prokaryotic and eukaryotic RNA polymerase i.e. All RNA polymerases are multi-protein complexes, however, the number of proteins that are assembled to form the active enzyme is much larger in eukaryotes; •The basic catalytic core is made up of 12 subunits. •By comparison, bacterial RNAP has 5 subunits. 01/23/15 70 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Rifampin, Rifamycin, Rifampicin, Rifabutin (bactericidal) • Mode of action - These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis. • Spectrum of activity - Broad spectrum but is used most commonly in the treatment of tuberculosis • Resistance – Common – For example; – Resistance to rifampicin develops quickly during treatment, so monotherapy should not be used to treat these infections — it should be used in combination with other antibiotics. – Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin. • Combination therapy - Since resistance is common, rifampin is usually used in combination therapy. 01/23/15 71 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Inhibitors of DNA Synthesis For this class of antibiotics, selectivity due to differences between prokaryotic and eukaryotic DNA replication enzymes Consider the following: Eukaryotic replication is more complicated. •First, they have multiple ori per chromosome that allow for bidirectional synthesis of the linear chromosome. •They also use several DNA polymerases (I, II, III), and ligase (seals the nicks in the DNA strand), and RNA primer (gives a 3' end for the DNA polymerase to start synthesis). •As for other differences in their synthesis of DNA is their speed, prokaryotes can replicate their chromosome at about 1,000 bp/sec, while eukaryotes can replicate their chromosomes at about 100 bp/sec. •They also differ in the number of ori, eukaryotes (as it was stated above) has multiple ori, while prokaryotes have only one. 01/23/15 72 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
The Quinolones • Current drugs are fluoridated 4-quinolones • Broad coverage (some broader than others) • Targets DNA gyrase ( G-) and topoisomerase IV (G+) • Resistance due to efflux and mutations in targets 01/23/15 73 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Pharmacological attributes of Quinolones • Favorable pharmacological attributes – Orally administered, quickly absorbed, even with a full stomach – Excellent bioavailability in a wide range of tissues and body fluids (including inside cells) • Mostly cleared by the kidneys – Exceptions are pefloxacin and moxifloxacin which are metabolized by liver • Ciprofloxacin, ofloxacin, and pefloxacin are excreted in breast milk ““Got Cipro?”Got Cipro?” 01/23/15 74 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Therapeutic Uses of Quinolones • Urinary tract infections • Prostatitis • STD’s – Chlamydia – Chancroid - painful sores on the genitalia – Not syphilis or gonorrhea (due to increased resistance) 01/23/15 75 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Therapeutic Uses of Quinolones • GI and abdominal – Travelers diarrhea – Shigellosis – Typhoid fever • Respiratory tract – New agents for strep. pneumonia 01/23/15 76 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Therapeutic Uses of Quinolones • Bone, joint, soft tissue – Ideal for chronic osteomylitis - infection of the bone or bone marrow • Resistance developing in S. aureus, P. aeruginosa, and S. marcesens – Good against polymicrobial infections like diabetic foot ulcers 01/23/15 77 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Therapeutic Uses of Quinolones • Ciprofloxacin for anthrax and tuleremia (rabbit fever, deer fly fever, Ohara's fever) • Combined with other drugs, useful for atypical Mycobacterium sp. Pulmonary AnthraxPulmonary Anthrax 01/23/15 78 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Toxicity/Contraindications of Quinolones • Nausea, vomiting, abdominal discomfort (common) • Diarrhea and antibiotic-associated colitis (uncommon to rare) • CNS side effects – Mild headache and dizziness (common to rare) – Hallucinations, delirium, and seizures (rare) • Arthropy in immature animals (common) – Quinolones not given to children unless benefits outweigh the risks • Leukopenia, eosinophilia, heart arythmias (rare) delirium - disorder involving incoherent speech, hallucinations, etc., caused by intoxication, fever, etc 01/23/15 79 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Antimetabolite Antibiotics 01/23/15 80 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Inhibitors of Folic Acid Synthesis • Basis of Selectivity • Review of Folic Acid Metabolism p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine Trimethoprim Sulfonamides 01/23/15 81 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Sulfonamides, Sulfones (bacteriostatic) • Mode of action - These antimicrobials are analogues of para- aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. • Spectrum of activity - Broad range activity against gram- positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. • Resistance - Common • Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains. 01/23/15 82 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Trimethoprim, Methotrexate, Pyrimethamine (bacteriostatic) • Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. • Spectrum of activity - Broad range activity against gram- positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. • Resistance - Common • Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains. 01/23/15 83 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Sulfonamides • Analogues of para-aminobenzoic acid • Broad spectrum • Competitive inhibitors of dihydropteroate synthase – needed for folic acid synthesis Gerhard Domagk gets a NobelGerhard Domagk gets a Nobel for Medicine, 1939.for Medicine, 1939. 01/23/15 84 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Sulfonamides • Mostly absorbed from GI tract • Binds variably to serum albumin • Wide tissue distribution, including transplacentally • Variably inactivated in liver by acetylation and then excreted in urine • Some agents can precipitate in acid urine 01/23/15 85 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
1. Rapidly Absorbed and Eliminated Sulfonamides • Sulfisoxazole, sulfamethoxazole, sulfadiazine • Bind extensively to plasma proteins • Highly concentrated in urine (cidal) • Sulfamethoxazole combined with trimethoprim (Bactrim) is widely used to treat a variety of infections (esp. UTI) 01/23/15 86 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
2. Poorly Absorbed Sulfonamides • E.g. Sulfasalazine • Poorly absorbed in GI tract • Used to treat ulcerative colitis and irritable bowel syndrome • Gut flora metabolize drug into 2 compounds, 1 toxic- sulfapyridine, 1 therapeutic (5-aminosalicylate) • Hence is a prodrug – effective after breakdown Ulcerative Colitis 01/23/15 87 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Sulfonamides for Topical Use • E.g. 1.Sulfacetamide – Good penetration in eye – Non-irritating • 2. Silver sulfadiazine – Prevention and treatment of burn wound infections Bacterial corneal infectionBacterial corneal infection 01/23/15 88 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Long Acting Sulfonamide • Serum half-life is measured in days rather than minutes or hours • E.g. Sulfadoxine • Combined with pyirethamine to treat malaria Plasmodium vivaxPlasmodium vivax 01/23/15 89 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Therapeutic Uses of Sulfonamides • Urinary tract infections • Nocardiosis -serious infection caused by a fungus-like bacterium that begins in the lungs and can spread to the brain. • Toxoplasmosis - caused by protozoan (avoid using in pregnant women) Nocardia asteroidesNocardia asteroides 01/23/15 90 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Toxicity/Contraindications of Sulfonamides - UT • Crystallization in acid urine – Common to uncommon depending on drug. – Alkalize urine or increase hydration 01/23/15 91 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Toxicity/Contraindications of Sulfonamides - blood • Acute hemolytic anemia – Rare to extremely rare – Associated with glucose-6-phosphate dehydrogenase activity in RBC • Agranulocytosis - failure of the bone marrow to make enough white blood cells (neutrophils). (extremely rare) • Aplastic anemia - marrow doesn't make enough new blood cells. (extremely rare) 01/23/15 92 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Toxicity/Contraindications of Sulfonamides - immune • Hypersensitivity reactions (common to uncommon) – Skin and mucous membrane manifestations (rashes) – Serum sickness - type III hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum – Focal or diffuse necrosis of the liver (rare) 01/23/15 93 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Toxic Epidermal Necrolysis (TEN) 01/23/15 94 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
Toxicity/Contraindications of Sulfonamides - miscellaneous • Nausea, anorexia, vomiting (common) • Kernicterus; damage caused by excessive jaundice – Displacement of bilirubin from plasma albumin to brain resulting in encephalopathy(disease of the brain) – Never give sulfa drugs to a pregnant or lactating woman • Potentiation of oral coagulants, sulfonylurea hypoglycemic drugs, and hydrantoin anticonvulsants Bilirubin deposits in neonatalBilirubin deposits in neonatal brainbrain 01/23/15 95 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
INJURY TO THE PLASMA MEMBRANE - Brief • All cells are bound by a cell membrane. • And although the membranes of all cells are quite similar, those of bacteria and fungi differ from eukaryotic cells. • These slight differences allow for selective action of some antimicrobial agents. • Certain antibiotics, like polymyxins, act as detergents to dissolve bacterial cell membranes by binding to phospholipids present in the membranes. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 96
The End Thank you for Listening 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 97

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Classes of antimicrobial agents

  • 1. MBSM 713: BIOCHEMISTRY OF ANTI MICROBIAL AGENTS Lecture Two: Survey of major antimicrobial drug groups 1.ANTIBACTERIAL AGENTS (Antibiotics) Dr. G. Kattam Maiyoh 01/23/15 1 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 2. Classification: Mode of action 01/23/15 2 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 3. Inhibitors of Cell Wall Synthesis 01/23/15 3 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 4. 01/23/15 4 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 Bacterial cell wall • There are three types – Gram-positive (e.g. Staphylococci, Listeria • Have many peptidoglycan layers • stains with crystal violet • typically lack the outer membrane found in gram-ve. – Gram-negative (e.g. E.coli, Salmonella) • Have few peptidoglycan layers • (stain safranin or fuchsin) – Acid-fast Positive (Mycobacteria) • Cell wall contains waxy substance (Mycollic acid) • Stains with acid fast (heating required)
  • 5. Antibiotics - Cell wall synthesis inhibitors Beta-lactam antibiotics: 1928 - Alexander Fleming observes the antibacterial effects of Penicillin 1940 - Florey and Chain extract Penicillin 01/23/15 5 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 6. The beta lactams • The β-lactam group of antibiotics includes an enormous diversity of natural and semi-synthetic compounds that inhibit several enzymes associated with the final step of peptidoglycan synthesis. • All of this enormous family are derived from a β -lactam structure: a four-membered ring in which the β -lactam bond resembles a peptide bond. • The multitude of chemical 01/23/15 6 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 8. Penicillinase (β Lactamase) - Represents a great challenge to the action of the beta lactams Figure 20.8 More when we discuss antibiotic resistance 01/23/15 8 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 9. • Penicillium notatum produces the only naturally occurring agent – penicillin G or benzylpenicillin • Penicillium chrysogenum produces 6-aminopenicillanic acid, raw material for semi-synthetics penicillins 01/23/15 9 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 10. Targets for beta lactams 1. The targets for β-lactam drugs are the penicillin binding proteins (PBP's), so called because they bind radioactive penicillin and can be detected by autoradiography of gels on which bacterial proteins have been separated electrophoretically. • The penicillin binding proteins have transpeptidase or carboxypeptidase activity and they act to regulate cell size and shape. • They are also involved in septum formation and cell division. Bacteria have several individual penicillin binding proteins, each with a separate function. • Conventionally these are numbered according to size, with PBP 1 as the largest protein. • The PBP 1 of one bacterium will not necessarily have the same function as the PBP 1 of a different organism. 01/23/15 10 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 11. Target 2. The β-lactam antibiotics also stimulate the activity of autolysins by inactivating an inhibitor => lysis • Autolysins are enzymes that are responsible for the natural turnover of cell wall polymers to permit growth of the cells. • Under normal conditions, these enzymes produce controlled weak points within the peptidoglycan structure to allow for expansion of the cell wall structure. • This activity is stimulated by β-lactams, causing a breakdown of peptidoglycan and leading to osmotic fragility of the cell and ultimately to cell lysis. 01/23/15 11 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 12. Penicillins - classification – Narrow spectrum – penicillinase sensitive – Narrow spectrum – penicillinase resistant – Broad spectrum penicillins – Extended-spectrum penicillins • Cephalosporines • Carbapenems • Monobactams • Vancomycin, Bacitracin 01/23/15 12 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 13. Penicllins (pharmacokinetics) • Attains therapeutic concentration in most tissues • However has poor CSF penetration • Renal excretion (Excretion) • Side effects: hypersensitivity, nephritis, neruotoxicity, platelet dysfunction 01/23/15 14 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 14. Narrow spectrum – penicillinase (= β-lactamase) sensitive • Benzylpenicillin – Naturally occuring – Poor oral availability (sensitive to stomach acid) => given by injection – Active against gram-positive bacteria • Phenoxymethylpenicillin – Better oral availability (acid resistant) 01/23/15 15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 15. Narrow spectrum – penicillinase (= β-lactamase) resistant • Methicillin – Semisynthetic – Poor oral availability (only parenteral) – Active against gram-pos bacteria – Mostly used for Staphylococcus aureus • Oxacillin – Good oral availability • Cloxacillin • Dicloxacillin 01/23/15 16 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 16. Broad spectrum – penicillinase (β- lactamase) sensitive (Also referred to as Aminopenicillins) • Ampicillin – Semisynthetic – Good oral availability – Active against gram-pos and gram-neg bacteria – Active against enterobacteria e.g. kleb. Shig. Salm • Amoxicillin – Excellent oral availability 01/23/15 17 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 17. Extended spectrum – penicillinase (β- lactamase) sensitive (Also called Carboxypenicillins) • Carbenicillin – Semisynthetic – Poor oral availability – Active against gram-pos and gram-neg bacteria – Active against Pseudomonas aeruginosa and Klebsiella • Ticarcillin • Mezlocillin • Pipercillin 01/23/15 18 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 20. Cephalosporins • Share the same antibiotic mechanism as penicillins • Cross-allergies with penicillins are common • Some CSs antagonize Vitamin K => leads to bleeding • Some CSs block alcohol oxidation => disulfiram effect (allergic reactions, seizures, extreme tiredness and dark urine) Classified into generations: 1- 4  • Increasing activity against gram-negative bacteria and anaerobes • Increasing resistance to destruction by beta-lactamases • Increasing ability to reach cerebrospinal fluid 01/23/15 21 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 21. Cephalosporins • The first to be discoverded were called first generation while later, more extended spectrum cephalosporins were classified as second, third and 4th generation cephalosporins in this order. • Each newer generation has significantly greater gram- negative antimicrobial properties than the preceding generation, • Most cases with decreased activity against gram- positive organisms. • Fourth generation cephalosporins, however, have true broad spectrum activity. 01/23/15 22 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 24. • Base molecule is 7- aminocephalosporanic acid produced by a Sardinian sewer mold • R groups determine spectrum of activity and pharmacological properties • Mechanism of action/resistance and class pharmacology is essentially the same as penicillins 01/23/15 25 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 25. First Generation Cephalosporins • Cefazolin, cephalexin, cephadroxil • Excellent against susceptible staph and strep • Modest activity against G -ve • Cefazolin given parentally, others orally • More than half of the drug is bound to plasma proteins • Excreted by kidneys unmetabolized • Good for staph and strep skin and soft tissue infections 01/23/15 26 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 26. Second Generation Cephalosporins • Include; – Cefaclor, – cefuroxime, – cefprozil • Modest activity against G+, increased activity against G-, works against anaerobes • Cefaclor and cefprozil given orally • Absorption and excretion same as first generation. • Good for treating respiratory tract infections, intra-abdominal infections, pelvic inflammatory disease, diabetic foot ulcers 01/23/15 27 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 27. Third Generation Cephalosporins • Ceftaxime, ceftriaxzone, cefoperazone, cefpodoxime • Broad spectrum killers • Drugs of choice for serious infections • No effect against Listeria and beta- lactamase producing pneumococci • Cefpodoxime given orally, others parentally • Most excreted by kidney • Therapeutic uses – Bacterial meningitis – Lyme disease – Life-threatening G -ve sepsis (infection) 01/23/15 28 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 28. Fourth Generation Cephalosporin – e.g.Cefepime –Have true broad spectrum activity ( and more beta-lactamases resistanc (effective against Gm+ and Gm-) –Given parentally, excellent penetration into CSF –Good for nosocomial infections 01/23/15 29 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 30. Toxicity/Contraindications of Cephalosporins • Hypersensitivity reactions (uncommon) essentially same as for penicillins • Cross-reaction between 2 classes 01/23/15 31 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 31. Inhibitors of Cell Wall Synthesis 01/23/15 33GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 32. Carbapenems • Beta-lactam ring is fused to a 5 member ring system • Effect on microbes and pharmacology of carbapenems similar to penicillins 01/23/15 34GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 33. Selected Carbapenems • Imipenem – Broad spectrum including anaerobes and Pseudomonas aeruginosa – Parentally administered – Must be combined with cilastatin to be absorbed – Excreted by kidneys • Meropenem, ertapenem, and doripenem are similar to imipenem but don’t need co- administration with cilastatin cilastatin chemical compound which inhibits the human enzyme dehydropeptidase 01/23/15 35GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 34. Toxicity/Contraindications of Carbapenems • Nausea and vomiting (common) • Hypersensitivity reactions (uncommon) – Essentially the same as for penicillins – Cross-reactivity is possible 01/23/15 36 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 35. Aztrenam – a monobactam • Monobactam - beta-lactam compounds wherein the beta-lactam ring is alone and not fused to another ring • Works only on Gm -ve, including Pseudomonas aeruginosa • Useful for treating G-ve infections that require a beta-lactam because it does not elicit hypersensitivity reactions 01/23/15 37GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 36. Beta-lactamase inhibitors a. Clavulanic acid – Irreversible inhibitor of β-lactamase – Good oral absorption – Combined with amoxicillin or ticarcillin b. Sulbactam 01/23/15 38GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 37. Peptide Antibiotics Peptide antibiotics are drugs with polypeptides structure Sub-group of Peptide Antibiotics Polymyxins e.g. »Polymyxin B »Colistin Glycopeptides e.g. »Vancomycin »Teicoplanin »Avoparcin Bacitracin Streptogramins Each drug group has its own mechanism of action 4 groups and 4 mechanism 01/23/15 39 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 38. PolymyxinsPolymyxins Drug members Polymyxin B Colistin (Polymyxin E) Mechanism of action Detergent-like action Damage to cell membrane function Bind to Lipopolysaccharides (LPS) and destroy outer membrane of Gram- negative bacteria Bactericidal Concentration-dependent Non-selective on bacterial membrane Spectrum of activity Gram-negative bacteria01/23/15 40 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 39. PolymyxinsPolymyxins • Pharmacokinetics –Not absorbed via GI tract –If injection, drug accumulated and slowly excreted • Toxicities –Highly toxic if systemic injection –Nephrotoxic –Neurotoxic • Clinical uses –Oral treatment – 01/23/15 41 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 40. GlycopeptidesGlycopeptides • Group members –Vancomycin • Antibacterial activity –Inhibition of cell wall synthesis –Active against Gram-positive bacteria • Not absorbed orally, must administered IV • High toxicity –Local irritation , ototoxicity, nephrotoxicity • Clinical uses –Hardly used in animals01/23/15 42 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 41. BacitracinBacitracin • Drug activity –Inhibit cell wall synthesis –Activity on Gram-positive bacteria –Bactericidal • Nephrotoxic if systemic injection • Clinical uses – the same as polymyxin –Oral – as growth promoter –Local or topical drugs 01/23/15 43 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 42. Antibiotics that Inhibit Protein Synthesis 01/23/15 44 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 43. Protein synthesis inhibitors – Aminoglycosides – Tetracyclins - Spectinomycin – Macrolides – Chloramphenicol – Clindamycin 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 45
  • 44. Inhibition of Protein Synthesis by Antibiotics Figure 20.4 01/23/15 46 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 45. Review of Initiation of Protein Synthesis 30S 1 3 2 GTP 1 2 3 GTP Initiation Factors mRNA 3 1 2 GTP 30S Initiation Complex f-met-tRNA Spectinomycin Aminoglycosides 1 2 GDP + Pi 50S 70S Initiation Complex AP 01/23/15 47 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 46. Review of Elongation of Protein Synthesis GTP AP Tu GTP Tu GDP Ts Ts Tu + GDP Ts Pi P ATetracycline AP Erythromycin Fusidic Acid Chloramphenicol G GTP G GDP + Pi G GDP AP + GTP 01/23/15 48 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 47. Antimicrobials that Bind to the 30S Ribosomal Subunit 01/23/15 49 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 48. a) Aminoglycosides (bactericidal) streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) • Mode of action - The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur. • They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. – By binding to the 16 S r-RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity. • May also destabilize bacterial membranes. 01/23/15 50 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 49. Microbe Library American Society for Microbiology www.microbelibrary.org 01/23/15 51 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 50. b) Aminoglycosides (bactericidal) streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) • Spectrum of Activity –Effective against many gram- negative and some gram-positive bacteria; • Not useful for anaerobic (oxygen required for uptake of antibiotic) or intracellular bacteria. • Resistance - Common • Synergy - The aminoglycosides synergize with β -lactam antibiotics. The β -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides. 01/23/15 52GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 51. c) Tetracyclines (bacteriostatic) tetracycline, minocycline and doxycycline • Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome. • Spectrum of activity - Broad spectrum; Useful against intracellular bacteria • Resistance - Common • Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth. 01/23/15 53 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 52. d) Spectinomycin (bacteriostatic) • Mode of action - Spectinomycin reversibly interferes with m-RNA interaction with the 30S ribosome. It is structurally similar to the aminoglycosides but does not cause misreading of mRNA. • Spectrum of activity - Used in the treatment of penicillin-resistant Neisseria gonorrhoeae • Resistance - Rare in Neisseria gonorrhoeae 01/23/15 54 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 53. Antimicrobials that Bind to the 50S Ribosomal Subunit 01/23/15 55 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 54. a) Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic) • Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. • Spectrum of activity - Chloramphenicol - Broad range; Lincomycin and clindamycin - Restricted range • Resistance - Common • Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis. 01/23/15 56 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 55. b) Macrolides (bacteriostatic) erythromycin, clarithromycin, azithromycin, spiramycin • Mode of action - The macrolides inhibit translocation. • Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella • Resistance - Common 01/23/15 57 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 56. Macrolides : ClassificationMacrolides : Classification • Macrolides are drugs with lactone ring structure • Sub-groups are based on no. of ring atom – 12-membered ring macrolides – 13-membered – 14-membered (many drugs) – 15-membered – 16-membered (many drugs) • Special groups – Azalides – name for 15-membered – Triamilides – name for tulathromycin (combination of 13- and 15-membered) – Ketolides – name for 14-membered with 3 keto group 01/23/15 58 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 57. MacrolidesMacrolides Drug examples 13-membered Tulathromycin (Triamilides) 14-membered Erythromycin Clarithromycin, Roxithromycin, Dirithromycin 15-membered Azithromycin (Azalides) Tulathromycin (Triamilides) 16-membered Spiramycin Tylosin 01/23/15 59 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 58. Macrolides – generalMacrolides – general propertiesproperties • Mechanism of action – Inhibit protein synthesis – Bind to 50S ribosomal unit – Bacteriostatic • Spectrum of activity – Gram-positive – Some Gram- negative 01/23/15 60 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 59. MacrolidesMacrolides Pharmacokinetics Broad distribution in body tissues High intracellular concentration 01/23/15 61 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 60. MacrolidesMacrolides Additional properties of Macrolides • Anti-inflammatory effect – Inhibitory effect on neutrophils – inhibit proinflammatory cytokines – Useful for treatment of inflammatory01/23/15 62 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 61. ErythromycinErythromycin • Erythromycin is a standard or basic drug of macrolides • Other drug members are usually compared with erythromycin • Important adverse effect - severe diarrhea – Especially in adult horse and ruminants • Clinical uses – Second choice (alternative drug) in humans – Small animals – Fowls 01/23/15 63 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 62. Tylosin andTylosin and SpiramycinSpiramycin • Tylosin and Spiramycin – Activities are similar to erythromycin – Good activity on Mycoplasma • Examples of Clinical uses – Whooping couph – Pneumonia – VDs – Used in ruminants01/23/15 64 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 63. Advanced generationAdvanced generation MacrolidesMacrolides Example drugs Roxithromycin Dirithromycin Clarithromycin Azithromycin General activity – the same as erythromycin Better Pharmacokinetic properties Acid stable Fewer GI side effect Higher oral availability Longer serum half-lives Higher tissue concentrations 01/23/15 65 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 64. KetolidesKetolides • Ketolides are 14- membered ring macrolides with 3 keto group • Specific drugs – Telithromycin – Cethromycin (still in clinical study) • Important properties – Less resistance – Good activities on01/23/15 66 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 65. Fusidic acid (bacteriostatic) • Selectivity due to differences in prokaryotic and eukaryotic elongation factors • Mode of action - Fusidic acid binds to elongation factor G (EF-G) and inhibits release of EF-G from the EF-G/GDP complex. • Spectrum of activity - Gram-positive cocci 01/23/15 67GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 Antimicrobials that Interfere with Elongation Factors
  • 66. Inhibitors of Nucleic Acid Synthesis ~Inhibitors of DNA synthesis ~Inhibitors of RNA synthesis 01/23/15 69 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 67. Inhibitors of RNA Synthesis For this class of antibiotics, selectivity is due to differences between prokaryotic and eukaryotic RNA polymerase i.e. All RNA polymerases are multi-protein complexes, however, the number of proteins that are assembled to form the active enzyme is much larger in eukaryotes; •The basic catalytic core is made up of 12 subunits. •By comparison, bacterial RNAP has 5 subunits. 01/23/15 70 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 68. Rifampin, Rifamycin, Rifampicin, Rifabutin (bactericidal) • Mode of action - These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis. • Spectrum of activity - Broad spectrum but is used most commonly in the treatment of tuberculosis • Resistance – Common – For example; – Resistance to rifampicin develops quickly during treatment, so monotherapy should not be used to treat these infections — it should be used in combination with other antibiotics. – Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin. • Combination therapy - Since resistance is common, rifampin is usually used in combination therapy. 01/23/15 71 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 69. Inhibitors of DNA Synthesis For this class of antibiotics, selectivity due to differences between prokaryotic and eukaryotic DNA replication enzymes Consider the following: Eukaryotic replication is more complicated. •First, they have multiple ori per chromosome that allow for bidirectional synthesis of the linear chromosome. •They also use several DNA polymerases (I, II, III), and ligase (seals the nicks in the DNA strand), and RNA primer (gives a 3' end for the DNA polymerase to start synthesis). •As for other differences in their synthesis of DNA is their speed, prokaryotes can replicate their chromosome at about 1,000 bp/sec, while eukaryotes can replicate their chromosomes at about 100 bp/sec. •They also differ in the number of ori, eukaryotes (as it was stated above) has multiple ori, while prokaryotes have only one. 01/23/15 72 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 70. The Quinolones • Current drugs are fluoridated 4-quinolones • Broad coverage (some broader than others) • Targets DNA gyrase ( G-) and topoisomerase IV (G+) • Resistance due to efflux and mutations in targets 01/23/15 73 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 71. Pharmacological attributes of Quinolones • Favorable pharmacological attributes – Orally administered, quickly absorbed, even with a full stomach – Excellent bioavailability in a wide range of tissues and body fluids (including inside cells) • Mostly cleared by the kidneys – Exceptions are pefloxacin and moxifloxacin which are metabolized by liver • Ciprofloxacin, ofloxacin, and pefloxacin are excreted in breast milk ““Got Cipro?”Got Cipro?” 01/23/15 74 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 72. Therapeutic Uses of Quinolones • Urinary tract infections • Prostatitis • STD’s – Chlamydia – Chancroid - painful sores on the genitalia – Not syphilis or gonorrhea (due to increased resistance) 01/23/15 75 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 73. Therapeutic Uses of Quinolones • GI and abdominal – Travelers diarrhea – Shigellosis – Typhoid fever • Respiratory tract – New agents for strep. pneumonia 01/23/15 76 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 74. Therapeutic Uses of Quinolones • Bone, joint, soft tissue – Ideal for chronic osteomylitis - infection of the bone or bone marrow • Resistance developing in S. aureus, P. aeruginosa, and S. marcesens – Good against polymicrobial infections like diabetic foot ulcers 01/23/15 77 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 75. Therapeutic Uses of Quinolones • Ciprofloxacin for anthrax and tuleremia (rabbit fever, deer fly fever, Ohara's fever) • Combined with other drugs, useful for atypical Mycobacterium sp. Pulmonary AnthraxPulmonary Anthrax 01/23/15 78 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 76. Toxicity/Contraindications of Quinolones • Nausea, vomiting, abdominal discomfort (common) • Diarrhea and antibiotic-associated colitis (uncommon to rare) • CNS side effects – Mild headache and dizziness (common to rare) – Hallucinations, delirium, and seizures (rare) • Arthropy in immature animals (common) – Quinolones not given to children unless benefits outweigh the risks • Leukopenia, eosinophilia, heart arythmias (rare) delirium - disorder involving incoherent speech, hallucinations, etc., caused by intoxication, fever, etc 01/23/15 79 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 78. Inhibitors of Folic Acid Synthesis • Basis of Selectivity • Review of Folic Acid Metabolism p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine Trimethoprim Sulfonamides 01/23/15 81 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 79. Sulfonamides, Sulfones (bacteriostatic) • Mode of action - These antimicrobials are analogues of para- aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. • Spectrum of activity - Broad range activity against gram- positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. • Resistance - Common • Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains. 01/23/15 82 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 80. Trimethoprim, Methotrexate, Pyrimethamine (bacteriostatic) • Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. • Spectrum of activity - Broad range activity against gram- positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. • Resistance - Common • Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains. 01/23/15 83 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 81. Sulfonamides • Analogues of para-aminobenzoic acid • Broad spectrum • Competitive inhibitors of dihydropteroate synthase – needed for folic acid synthesis Gerhard Domagk gets a NobelGerhard Domagk gets a Nobel for Medicine, 1939.for Medicine, 1939. 01/23/15 84 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 82. Sulfonamides • Mostly absorbed from GI tract • Binds variably to serum albumin • Wide tissue distribution, including transplacentally • Variably inactivated in liver by acetylation and then excreted in urine • Some agents can precipitate in acid urine 01/23/15 85 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 83. 1. Rapidly Absorbed and Eliminated Sulfonamides • Sulfisoxazole, sulfamethoxazole, sulfadiazine • Bind extensively to plasma proteins • Highly concentrated in urine (cidal) • Sulfamethoxazole combined with trimethoprim (Bactrim) is widely used to treat a variety of infections (esp. UTI) 01/23/15 86 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 84. 2. Poorly Absorbed Sulfonamides • E.g. Sulfasalazine • Poorly absorbed in GI tract • Used to treat ulcerative colitis and irritable bowel syndrome • Gut flora metabolize drug into 2 compounds, 1 toxic- sulfapyridine, 1 therapeutic (5-aminosalicylate) • Hence is a prodrug – effective after breakdown Ulcerative Colitis 01/23/15 87 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 85. Sulfonamides for Topical Use • E.g. 1.Sulfacetamide – Good penetration in eye – Non-irritating • 2. Silver sulfadiazine – Prevention and treatment of burn wound infections Bacterial corneal infectionBacterial corneal infection 01/23/15 88 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 86. Long Acting Sulfonamide • Serum half-life is measured in days rather than minutes or hours • E.g. Sulfadoxine • Combined with pyirethamine to treat malaria Plasmodium vivaxPlasmodium vivax 01/23/15 89 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 87. Therapeutic Uses of Sulfonamides • Urinary tract infections • Nocardiosis -serious infection caused by a fungus-like bacterium that begins in the lungs and can spread to the brain. • Toxoplasmosis - caused by protozoan (avoid using in pregnant women) Nocardia asteroidesNocardia asteroides 01/23/15 90 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 88. Toxicity/Contraindications of Sulfonamides - UT • Crystallization in acid urine – Common to uncommon depending on drug. – Alkalize urine or increase hydration 01/23/15 91 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 89. Toxicity/Contraindications of Sulfonamides - blood • Acute hemolytic anemia – Rare to extremely rare – Associated with glucose-6-phosphate dehydrogenase activity in RBC • Agranulocytosis - failure of the bone marrow to make enough white blood cells (neutrophils). (extremely rare) • Aplastic anemia - marrow doesn't make enough new blood cells. (extremely rare) 01/23/15 92 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 90. Toxicity/Contraindications of Sulfonamides - immune • Hypersensitivity reactions (common to uncommon) – Skin and mucous membrane manifestations (rashes) – Serum sickness - type III hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum – Focal or diffuse necrosis of the liver (rare) 01/23/15 93 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 91. Toxic Epidermal Necrolysis (TEN) 01/23/15 94 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 92. Toxicity/Contraindications of Sulfonamides - miscellaneous • Nausea, anorexia, vomiting (common) • Kernicterus; damage caused by excessive jaundice – Displacement of bilirubin from plasma albumin to brain resulting in encephalopathy(disease of the brain) – Never give sulfa drugs to a pregnant or lactating woman • Potentiation of oral coagulants, sulfonylurea hypoglycemic drugs, and hydrantoin anticonvulsants Bilirubin deposits in neonatalBilirubin deposits in neonatal brainbrain 01/23/15 95 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02
  • 93. INJURY TO THE PLASMA MEMBRANE - Brief • All cells are bound by a cell membrane. • And although the membranes of all cells are quite similar, those of bacteria and fungi differ from eukaryotic cells. • These slight differences allow for selective action of some antimicrobial agents. • Certain antibiotics, like polymyxins, act as detergents to dissolve bacterial cell membranes by binding to phospholipids present in the membranes. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 96
  • 94. The End Thank you for Listening 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC02 97