Protein Synthesis Antibacterials for Class 2016 PDF

Antibacterials That Inhibit Protein Synthesis Tetracycline Aminoglycosides Macrolides Miscelanius By FA 2 By FA 3 Mechanism of Action of Protein Synthesis Inhibitors Active sites of ribosomes are made of RNA Ribosomes have been classified as ribozymes the proteins organize the whole and...

Antibacterials That Inhibit Protein Synthesis Tetracycline Aminoglycosides Macrolides Miscelanius By FA 2 By FA 3 Mechanism of Action of Protein Synthesis Inhibitors Active sites of ribosomes are made of RNA Ribosomes have been classified as ribozymes the proteins organize the whole and catalyze some part of the biosynthetic cycle Ribosomes have 2 main tRNA binding sites: A (acceptor) and P (peptidyl) By FA 4 By FA 5  Tetracycline… The tetracyclines are also often used in combination with other agents for the treatment of peptic ulcer disease caused by Helicobacter pylori infection. Doxycycline is also used for chemoprophylaxis of malaria under certain conditions. As the name suggests, tetracyclines possess four rings that form the minimal naphthacene tetracycle. By FA 6  SAR of Tetracycline No changes can be made to the southern and eastern faces of molecule 4-position dimethylamino function is essential for activity and the a- epimer is much more potent than the b-epimer Activity is largely retained in primary and secondary amines but rapidly decreases in higher alkylamines 5-position; can have a hydroxyl group, keto group or a hydrogen; all are active. 6-position; no substitution is necessary. 7-position accommodates a range of substitutions e.g. Cl, F, Br, NO2, a tertiary amine, aminomethyl derivatives, substituted and unsubstituted aromatic rings 8-position; substitution with any electron withdrawing or donating group is still active By FA 7  Tetracyclin… The natural products tetracycline , chlortetracycline , oxytetracycline , demethylchlortetracyline , and the semisynthetic minocycline and doxycycline are frequently used. Chlortetracycline Tetracycline Oxytetracyclines demethylchlortetracycline By FA 8  Tetracycline… Minocycline doxycycline Tigecycline (Tygacil®) The latest of the tetracyclines in the market Also classified as glycylcycline Addresses some resistance issues Effective against gram (+) and gram (-) bacteria, anaerobes, and MRSA Used for the treatment of complicated skin and skin structure as well as complicated intra-abdominal infections By FA 9 Tigecycline (Tygacil®)  Chemical Properties of Tetracyclines are amphoteric substances with three pKa values shown by titration: 2.8-3.4, 7.2–7.8, and 9.1–9.7 have an isoelectric point at approximately pH 5 The basic function is the C-4-α-dimethylamino moiety In general tetracyclines are administered as comparatively water- soluble hydrochloride salts The conjugated systems (C10-C12 and C1-C3) can be drawn in a number of equivalent ways with the double bonds in alternate positions pKa = 9.1-9.7 3 4 2 conjugated 10 11 12 1 conjugated trione system phenolic enone pKa = ~7.5 pKa = ~3 By FA 10 Chelation important feature of the chemical and clinical properties of the tetracyclines acidic functions of the tetracyclines are capable of forming salts through chelation with metal ions salts of divalent and trivalent metal ions, such as Fe2+, Ca2+, Mg2+, and Al3+, are all quite insoluble at neutral pHs The insolubility interferes with absorption leading to low blood levels on oral administration As a result, the tetracyclines are incompatible with coadministered antacids, hematinics, dairy products rich in calcium ion By FA 11 Epimerization An epimer is a diastereomer that differs in configuration of only one chiral center The α-stereo orientation of the C-4 dimethylamino group of the tetracyclines is essential for their antimicrobial activity The presence of the tricarbonyl system of ring A allows enolization resulting in loss of the C-4 hydrogen Addition of a proton (H+) to the enol may take from either the top or bottom of the molecule Addition of the proton from the top results in the active epimer (a-epimer) while addition from the bottom results in the inactive epimer (b-epimer) the mixture consists of nearly equal amounts of the two diasteromers at equilibrium Therefore, old tetracycline preparations can lose their potency in this way By FA 12 Dehydration Tetracycline derivatives such as tetracycline that contain benzylic hydroxyl group at C-6 are prone to acid-catalyzed dehydration The resulting anhydrotetracycline is much deeper in color than tetracycline and is biologically inactive Discoloration of old tetracycline might be due to this degradation product and should be discarded This degradation product is toxic to the kidneys and produces a Fanconi-like syndrome Commercial samples of tetracyclines are closely monitored for the presence of 4-epidehydrotetracycline By FA 13 Base-catalyzed Cleavage Compounds containing a C-6-hydroxyl group can also undergo C- ring cleavage in alkaline solutions at or above pH 8.5 The degradation product, an isotetracycline, is inactive and the clinical impact of this molecule is not known The instability of tetracycline and other derivatives that contain 6- OH has led to the search for more stable and longer acting compounds such as doxycycline and minocycline, compounds with no 6-OH group By FA 14  Tetracycline…  As predicted by structure-activity studies, all four rings of tetracycline participate in binding to the ribosome and, in particular, Ring D stacks with the pyrimidine ring of C1054.  The entire pharmocophore region of the molecule is involved in specific interactions with the 30s rRNA  Mg+ is also present in the structure of the ribosome in the absence of antibiotic and may represent a key conserved binding element  Work by inhibiting the 30S ribosomal subunit of the bacteria By FA 15  Tetracycline Tetracycline antibiotics are no longer used for empirical treatment of many Gram-negative and Gram-positive infections as a result of the dissemination and prevalence of resistance. Tetracyclines are absorbed in the gastrointestinal tract and are subsequently widely distributed in most tissues. These antibiotics also cross the placenta and are present in breast milk – Therefore are not recommended for pregnant or lactating women. Most tetracycline antibiotics are eliminated through the kidney – therefore not recommended for patients with renal problems The exception is Doxycycline, which is excreted through the bile. – Serum half-lives are long (6 to >20 h, depending on the agents) and thus once or twice daily dosing is recommended on the order of 100 mg per dose. Metabolism of these antibiotics is minimal. TTCs are painful Upon IM. This has been attributed to impart the information of insoluble calcium complexes  Injectable formulation contains EDTA and buffered at acidic PH By FA 16 By FA 17  Bacterial Resistance to Tetracyclines Ribosomal protection (protection of the ribosomes from the action of tetracycline) involves over- expression of bacterial proteins These proteins associate with ribosome, thus permitting protein synthesis in the presence of tetracycline Energy-dependent efflux of tetracycline from the bacterial cell Resistance to one tetracycline usually results in resistance to all tetracyclines By FA 18  II. Amino glycoside Antibiotics Antibiotics contain an aminocyclitol moiety to which aminosugars are glycosidically linked. They may be more correctly called aminocyclitol antibiotics. Introduced in 1944 by Selman Waksman after screening Streptomyces species (spp.) for antibiotics Mostly isolated from Streptomyces genus (-mycin) or Micromonospora genus (-micin). Composed of a sugar and an amino group (aminosugars) linked by glycosidic bonds R1 O HO H2N HO R2 O NH2 HO HO O O OH O NH2 ByH FA 19 Aminocyclitols  Cyclohexanes with several substituted or unsubstituted amino and hydroxyl groups which bring them high water solubility.  Streptidine and Streptamine can be called 1,3-diguanidino and 1,3-diamino inositol, respectively. HO HO 5 4 4 OH 5 OH 6 H 6 HO 3 N NH2 HO NH2 3 2 2 HN 1 OH H2N 1 OH H2N NH Streptamine NH Streptidine H2N NHCH3 HO 4 1 6 HO OH 5 OH 4 6 2 6 5 OH HO HO NH2 3 NHCH3 4 3 2 HO 5 H2N 1 3 2 1 OH H3CO 2-Deoxystreptamine Spectinamine Fortamine By FA 20  Aminoglycosides The aminoglycoside antibiotics find use as broad- spectrum agents for the treatment of infections caused by Aerobic Gram-negative and Gram-positive bacteria including – Klebsiella pneumoniae – Pseudomonas aeruginosa, – E. coli – Proteus sp. – Serratia marcescens and Staphylococci Streptomycin was the first aminoglycoside isolated and the first antibiotic with potent activity against Mycobacterium tuberculosis and this antibiotic continue to be used to treat tuberculosis. But as a result of the development of resistance, now it is used in combination therapy with other antibiotics By FA 21  SAR of Aminoglycosides Ring I Ring I: Ring II crucial for broad spectrum activity 2 Primary target of inactivating enzymes 1 Ring II: 3 many modifications are allowed such as substitution or acetylation of the 1-amino Ring III group Ring III: least sensitive for modifications By FA 22  Specific Aminoglycosides Kanamycin (Kantrex) Kanamycin (Kantrex) A mixture of at least three components (A, B, and C, with A predominating) Commercially available is almost pure kanamycin A, the least toxic of the three is among the most chemically stable of the common antibiotics can be heated without loss of activity in acid or alkaline solutions and can even withstand autoclaving temperatures It is also N-acetylated on the C-6′amino group resulting in inactive compounds Used parenterally against some gram (-) bacteria P. aeruginosa and anaerobes are usually resistant By FA 23  Kanamycins with different modification 4`-deoxy derivative ANT Resistant 6' R1H2C 5' O HO 4' 1' 2-Deoxystreptamine 3`-deoxy derivative HO 3' 2 ' H2N II APH Resistant I R2 2 O 3 4 NH2 5 6 1 Kanosamine HO O 6'' 5'' 1'' HOH2C O OH HO 4'' 3'' 2'' NH2 III Kanamycin A: R1= NH2 ; R2 = OH Kanamycin B: R1 = NH2 ; R2 = NH2 Kanamycin C: R1= OH; R2 = NH2 By FA 24  Specific Aminoglycosides Amikacin (Amikin) Is a semisynthetic derivative of kanamycin A The L-hydroxyaminobutyryl amide (HABA) moiety attached to N-3 inhibits adenylation and phosphorylation in the distant amino sugar ring (Ring I, at C-2′ and C-3′) This is due to decreased binding to the R factor–mediated enzymes The HABA group enhances both potency and spectrum of activity used for the treatment of sensitive strains of Mycobacterium tuberculosis, Yersinia tularensis, and severe Pseudomonas aeruginosa infections resistant to other agents By FA 25  Amikacin (Amikin) 6' 2-Deoxystreptamine H2NH2C 5' O HO 4' HO ' 1' O OH 3' 2 H2N OH 2 O 3 4 NH C C CH2 CH2 NH2 2 5 6 1 H HO O Kanosamine 5'' 6'' 1'' HOH2C O OH HO 4'' 3'' 2'' NH2 Amikacin, L-AHBA derivative of Kanamycin A By FA 26  Specific Aminoglycosides Gentamicin (Garamycin®) is a mixture of several antibiotic components produced by fermentation of Micromonospora purpurea and other soil microorganisms Gentamicins C-1, C-1a, and C-2 are the major constituents is the most important of the aminoglycoside antibiotics still in use The Lack of the 3- and 4-position hydroxyl groups enhances the spectrum of activity Effective against most gram (+) and (-) bacteria, including Pseudomonas Sp. By FA 27  Gentamicins with different modification Secondary amino group at 6`-NH2 in Gentamycin C1, spacial hynderance AAC Resisistant R1 6' NHR2 HC 5' O I 4' 1' 2-Deoxystreptamine 2 ' II Lacks 3`-OH 3' H2N NH2 2 APH Resistant O 3 NH2 4 5 6 1 Garosamine HO O 5'' 1'' O OH III H3C 4'' 3'' 2'' NH OH Gentamicin C1: R1=R2 = CH3 CH3 Gentamicin C2: R1 = CH3 ; R2 = H Gentamicin C1a: R1=R2 = H Axial and tertiary 4``-OH instead of equatorial secondary 4``-OH in Kanamycin ANT Resistant By FA 28  Specific Aminoglycosides Tobramycin (Nebcin®, Tobi®) It lacks the C-3′ hydroxyl group and as result it is not a substrate for APH(3′)-1 and APH(3′)-II Has an intrinsically broader spectrum than kanamycin it is a substrate, for adenylation and acetylation at other positions It used parenterally to treat difficult infections, particularly those caused by gentamicin-resistant Pseudomonas aeruginosa Used by inhalation to treat P. aeruginosa infections in cystic fibrosis patients It is thought to be less toxic than gentamicin By FA 29  Tobramicin 6' NH2 H2C 5' O HO 4' 1' 2-Deoxystreptamine ' 3' 2 H2N Lack 3`-OH NH2 2 O 3 NH2 APH Resistant 4 5 6 1 HO O 6'' 5'' 1'' HOH2C O OH HO 4'' 3'' 2'' NH2 Tobramycin By FA 30 Streptomycin was introduced primarily for the treatment of tuberculosis differs from the typical aminoglycosides in that the diaminoinositol unit is streptamine with a modified pharmacophore Has two highly basic guanido groups at C-l and C-3 in place of the primary amine moieties of 2-deoxystreptamine the unusual pharmacophore of streptomycin may account for its unusual antibacterial spectrum Aldehyde Streptamine By FA 31 Streptomycin the α-hydroxyaldehyde moiety makes the compound unstable to sterilization by autoclaving streptomycin sulfate solutions are sterilized by ultra filtration Used parenterally in treatment of TB (in combination with other agents), plague (Yersinia pestis an aerobic, gram negative bacilli), and GIT infections Resistance to streptomycin results from N-acetylation, O-phosphorylation, and O- adenylation of specific functional groups Aldehyde Streptamine By FA 32  Streptomicin is Isolated from cultures of Streptomyces griseus. – generally is less active than other members of the class against aerobic gram-negative rods. – Similar to gentamicin, with activity against some gentamicin- resistant enterococci. – The combination of penicillin G and streptomycin is effective for enterococcal endocarditis. – Activity against Mycobacterium tuberculosis  Streptomycin has been replaced by gentamicin for most indications because the toxicity of gentamicin is primarily renal and reversible, whereas that of streptomycin is vestibular and irreversible By FA 33  May be used in combination with β-lactams for synergism But it is chemically incompatible with certain β-lactams Should not be mixed in the same solution and should be administered into different tissue compartments (usually one in each arm) to prevent this A chemical drug–drug incompatibility between gentamicin C-2a and β-lactams By FA 34 By FA 35 By FA 36  Bacterial Resistance to Aminoglycosides Most important mechanism involves Production of bacterial enzymes that inactivate the aminoglycosides and includes: 1. Aminoglycoside acetylase (AAC) – N-acetylates the amino groups at 2’ and 6’ of ring I and 3 of ring II 2. Aminoglycoside phosphorylase (APH) - O-phosphorylation of hydroxyl groups phosphorylates 3`-OH of the ring I and 2``-OH of the ring III. 3. Aminoglycoside nucleotide transferase (ANT) – O-adenylates hydroxyl groups adenylates 2``,4``-OH of the ring III and 4`-OH of the ring I. These enzymatic transformation subsequently prevents ribosomal binding Other mechanism of resistance include mutations in A site that decrease affinity for aminoglycoside and decreased cell permeability Decreased uptake of the drug in some strains of p. aeroginosa in hospital infections because of blockade in the active transport of aminoglycosides. Aminoglycoside molecules attach through their cationic groups to anionic portions of membrane phospholipids of bacteria. Upon this attachment the ATP-dependent uptake occurs. Bivalent cations such as Ca2+ and Mg2+ compete with the drug in this process and antagonise them. Anaerobic bacteria lack the ATP-dependent uptake process, so they are resistant to aminoglycosides. By FA 37  Aminoglycosides can be modified so that they are not affected by inactivating enzymes but still retain intrinsic broad spectrum activity The structural modifications include: (i) Removal of affected functional groups transformed by these enzymes (ii) Attachment of novel functional groups that converts these antibiotics to poorer substrates of the enzymes By FA 38  Aminoglycoside Therapeutics Have broad antibiotic spectra against aerobic Gram-positive and Gram-negative bacteria are reserved for use in serious infections caused by Gram-negative organisms because of serious toxicities that often are delayed in onset Streptomycin and spectinomycin differ from the others in their useful antimicrobial spectra Streptomycin is most commonly used for the treatment of tuberculosis and spectinomycin for treatment of gonorrhea The other antibiotics of this class are inferior for the treatment of tuberculosis and gonorrhea By FA 39 Adverse Effects of Aminoglycosides Ototoxicity due to neurotoxicity of the 8th cranial nerve, can lead to vertigo and irreversible deafness Nephrotoxicity Toxic effects are related to blood levels, and mediated by the affinity of aminoglycosides for sensory cells of the inner ear and kidney cells Less common adverse effect is curare-like neuromuscular blockade and exaggerates muscle weakness in patients with myasthenia gravis or Parkinson’s disease By FA 40 By FA 41 By FA 42 5 common chemical features they are  Macro cyclic lactone, Usually, the lactone ring has 12, 14, or 16 atoms in it  A ketone group  One or two aminosugars linked to the nucleus.  A Neutral sugar linked either to amino sugar or to lactone ring  The presence of the dimethyl amino moiety on the sugar residue, which explains the basicity of these compounds and consequently formation salts By FA 43  Properties of Macrolide  They are stable in aqueous solutions at or below room temperature  They are unstable under acidic conditions &undergo an intramolecular reactions to form an inactive cyclic ketone By FA 44  Macrolides Picromycin, the first member of this group, was identified in1950 Followed by the discovery of erythromycin and carbomycin in 1952 One of the sugars has a substituted amino group, making the molecules weakly basic (pKa ~ 8) The erythromycin class are chemically unstable because of rapid acid- catalyzed intramolecular cyclic ketal formation, resulting in loss of activity 9 10 8 Erythromycin, R = H 7 11 6 Erythromycin estolate, R = 4 5 COCH2CH3 1 2 3 Desosamine Erythromycin ethylsuccinate, R = COCH2CO2CH2CH3 Erythromicin stearate, R= stearic acid residuee-coating on acidic environment cladinose By FA 45 Clarithromycin (Biaxin) Is the 6-methyl ether of erythromycin Methylation of the 6-hydroxyl group results in marked increased in acid-stability and oral bioavailability while it retains the full antibacterial activity Clarithromycin has also reduced GI side-effects associated with erythromycin Similar coverage as erythromycin with greater potency, especially against H. influenzae Is metabolized in the liver via oxidation and hydrolysis of the lactone By FA 46 Azithromycin (Zithromax, Zmax) 11 8 7 A ring-expanded analogue of erythromycin 13 5 The carbonyl moiety is absent 15 1 3 (reduced to methylene group) The removal of the 9-keto group along with the addition of a weakly basic 3º amine into the macrolide ring increased the acid-stability of azithromycin has a considerably longer half-life, attributed to greater and longer tissue penetration, allowing once-a-day dosage broader spectrum than either erythromycin or clarithromycin Postantibiotic effect The greater activity against H.influenzae, M. catarrhalis, and M. Pneumonae coupled with longer half-life allows a 5-day dosing schedule for the treatment of respiratory tract infections By FA 47  Chloramphenicol First broad-spectrum oral antibiotic used in the U.S. (1947) Binds to 50S ribosomal subunit in a region near where macrolides Limited use to treat typhoid fever (Salmonella enterica serovar Typhi), Haemophilus, and rickettsial infections due to toxicities Chloramphenicol By FA 48 By FA 49 By FA 50 By FA 51 By FA 52 53 By FA 54 By FA 55 By FA 56 By FA 57  Chiral center Ofloxacin (Floxin®) Levofloxacin (Levaquin®) Norfloxacin (Noroxin®) 3 4 2 1 Lomefloxacin Alkyl sparfloxacin substituents By FA 58 By FA 59 Waiting for Exam? By FA 60