Lecture 5 - Non-Beta-Lactam Antibiotics PDF

Non-β-lactam antibiotics Antibacterial agents which impair protein synthesis  Antibacterial agents which impair protein synthesis 1. Tetracycline 2. Chloramphenicol 3. Aminoglycosides...

Non-β-lactam antibiotics Antibacterial agents which impair protein synthesis  Antibacterial agents which impair protein synthesis 1. Tetracycline 2. Chloramphenicol 3. Aminoglycosides 4. Macrolide  They inhibit protein synthesis by binding to ribosomal RNA,  their selectivity is due to 1) Difference in diffusion rates trough bacterial and mammalian cell 2) Difference between structures of the ribosomal targets 50S 60S Prokaryotic 70S Eukaryotic 80S 30S 40S Tetracycline H3C CH3 CH3 N OH H  Bacteriostatic OH  Broad spectrum of activity D C B A 10 11 12 2 NH2  Antimalarial 1 OH  Derived from streptomyces species OH O OH O O Has naphthacene ring MOA  Bacteriostatic: Interfere with protein synthesis by binding to 30S subunit  Bactericidal: are high lipophilic compounds disrupting cytoplasmic membrane ► leakage of essential cellular component  in gram –ve: pass through outer membrane by passive diffusion through pores  Selectivity is due to the ability of bacteria to concentrate these agent faster than mammalian cell (tetracycline can inhibit mammalian protein synthesis) Therapeutic uses 1. URT infection 2. Acne Tetracycline derivatives X CH3 H N(CH3)2 HO H OH NH2 OH OH O OH O O Generic name x Nature Notes Tetracycline H Natural Chlorotetracycline Cl Natural Used as HCl salt Rolitetracycline N-pyrrolidinomethyl Semi- Highly water soluble tetracycline synthetic Oral & parentral use  Not used with Ca, Fe or Mg because it form insoluble chelate with polyvalent ions  Painful on I.M. injection due to formation of Ca complex so we must add EDTA  Not recommended for children (6-12 years old) due to deposition of drug in teeth forming permanent discoloration  Not prescribed during pregnancy or lactation  [I] Natural Tetracyclines H3C CH3  Produced by fermentation of Streptomyces OH N H3C H H aureofaciens OH OH  Most widely used, cheap antibiotic. NH2  Its blood level after oral administration is irregular; due to inactivation by acidic medium in OH O OH O O stomach or basic medium in intestine.  The drug of 1st choice in ACNE. Tetracycline H3 C CH 3 OH OH N H3 C H OH  [Terramycin®] OH  Produced by fermentation of Streptomyces CONH 2 OH O OH O rimosis & other soil m.o.  The most hydrophilic tetracycline. Oxytetracycline Poor oral absorption of tetracycline & oxytetracycline is due to: 1. difficulty to penetrate lipid membranes(more water-soluble derivatives). 2. complexation with metal ions in the gut. 3. undergo acid-catalyzed destruction in the stomach.  [II] Semi-synthetic ® Tetracycline Doxycycline [ Vibramycin ] Minocycline (Minocin) H3C CH3 H3C CH3 H3 C CH3 H OH N N N H2 C H H OH 7 OH OH 6 OH CONH2 CONH2 OH O OH O OH O OH O 6-demethyl-6-deoxy-7-N- 6-deoxy-5-oxytetracycline dimethylaminotetracycline One of most important More lipophilic  give excellent blood tetracyclines. levels following oral administration.  Its metabolite is preferentially Given once daily [long duration]. excreted via bile into faces [ With Broad spectrum [effective ≠ strains EXCEPTION ]**. that resist methacillin & other  Can be given to uremic tetracyclines. patients with infections outside Less painful upon I.M. or I.V. injection. urinary tract. Stable ≠ acids & bases [why? NO 6-  It causes  GIT disturbance. OH].  The 6a-methyl epimer is more Side Effects : Vestibular toxicities than three times as active as b- [vertigo , ataxia , nausea]. epimer Chloramphenicol Cl O CH2OH Antimicrobial activity Cl HN H  Active # gram +ve & -ve & Some viruses H OH  The drug of choice for treatment of typhoid  Eye infection  MOA: Bind to 50S → inhibition of protein synthesis NO2  Physical problem : has very bitter taste overcomed by the use of palmitate ester Side effects 1. It should be used with restricted condition (toxic to bone marrow) 2. Gray baby syndrome SAR: 1. Only the D(-)-threo isomer is active 2. Replacement of 4-NO2 gp with –CN, OH Br groups give inactive compounds  The following are active compounds : Cetophenicaol Chloramphenicol O Cl O H NH C CH O NH C CH(Cl)2 3 Cl 1 1 2 H3C C CH2 OH O2N CH2 OH 2 3 OH H OH Thiamphenicol Azidamphenicol O O NH CH 2 N3 NH C CH(Cl)2 1 1 H3C S 2 CH2 OH O2 N CH2 OH 3 2 3 OH OH O  Prodrugs of chloramphenicol: [C3-esters] Chloramphenicol Chloramphenicol Palmitate Hemisuccinate O Cl O Cl H NH C CH H NH C CH 3 Cl Cl 1 2 1 2 3 O2N CH2 O CO CH2 CH2 COOH O2N CH2 O CO (CH2)14 CH3 OH H OH H  Insoluble in water.  Water soluble  used for  To overcome bitter taste. injection to overcome poor  Used for pediatric oral water solubility. suspensions. Esters are inactive  hydrolyzed in vivo releasing active form. Aminoglycosides (aminocyclitols)  They are effective against gram +ve, -ve & mycobacteria  They can not pass BBB (not used in treatment of meningitis) MOA:  They are bacteriocidal than bacteriostatic  The bind to 30S ► protein synthesis Streptomycin  Isolated from Streptomyces griseous  the first effective agent in treatment of TB  Can not be sterilized by autoclaving but by ultrafilteration  Aminoglycosides antibacterial antibiotics  Prototype of this class [first one used] is Streptomycin. General properties:  They are BACTERICIDAL, effective only ≠ aerobic bacteria [they are inactive ≠ anaerobic bacteria].  Although broad spectrum, but of limited use, for only severe G-ve infections due to their  toxicity [cause ototoxicity & nephrotoxicity by action on 8th cranial nerve].  In addition, paromomycin inhibits Entamoeba histolytica.  Very poorly absorbed from GIT [highly polar compounds]  when used orally it's intended for local GIT infections. But given I.M. for systemic infections(Freely water soluble ).  Neomycin has been used topically or orally in the treatment of intestinal infections & not given parentrally [ toxicity].  Aminoglycosides + -lactams  synergism but must not be combined in the same solution [should be given into different tissue compartments, as given each preparation one in each arm]  they are chemically incompatible. Chemical properties:  They have 3 pharmacophoric groups : H2N NH H2N H3 C-HN HO HN 2 HO HO HO 3 OH HO NH NH2 HO NH 2 HO NH CH 3 1 Streptidine OH NH 2-deoxy streptamine OH Spectinamine OH  Alcoholic functions of these moieties [OH]  make glycosidic bonds with amino sugars [aminoglycosides].  They are usually formed of 3 rings, freely soluble in water [why?]  They are basic [due to amino group], form acid addition salts.  All have at least one aminohexose and some have a pentose lacking an amino group e.g. streptomycin.  Each contains a substituted 1,3-diaminocyclohexane central ring: it is deoxystreptamine in kanamycin, neomycin, gentamicin, and tobramycin, and it is streptidine in streptomycin.  [I] Aminoglycosides containing Streptidine Streptomycin  Produced by fermentation OH NH-CH of Sterptomyces griseus & HO 3 HN 2 NH related soil m.o. HOH C O HN 2  Introduced primarily for O O OH NH NH treatment of T.B.[ may be N-methyl glucosamine [amino sugar] HO OH 2 CH O 3 HO NH due to presence of 2 OHC Streptidine guanido moieties]. But -CH2-OH [Pharmacophore] L-Streptose Dihydro Streptomycin replaced now by other [neutral sugar] antibiotics as Rifampin. Dihydro streptomycin:  Formed by replacing aldehydic group in L-streptose moiety by alchoholic group [CH2OH]  With greater probability > streptomycin to cause delayed deafness.  [II] Aminoglycosides containing 2-deoxy Streptamine Kanamycin NH2 Ac 4' 6' 5' O Ad HO HO 1' H 3' 2' OH 4 H N O 2 3 2 Phos 6 1 NH2 HO 5 O Glycosidic linkage 5'' 1'' HO 6'' O OH Kanmycin A HO 3'' 4'' H 2N 2''  Isolated from Streptomyces kanamyceticus  mixture of Kanamycin A, B & C.  Commercial one is pure Kanamycin A [the least toxic of them].  Chemically stable within pH 2-11, very stable to heat [sterilized by autoclaving].  Unstable to R-factor enzymes: [giving INACTIVE compounds]  3'-OH  Phosphorylation. 4'-OH  Adenylation. 6'-NH2  Acetylation. To improve its activity  SEMI-SYNTHETIC PRODUCTS by: 1) Adding functional group that prevent enzymatic attack. 2) Removal of susceptible functional groups which are not important for activity. Amikacin [Amikin®]  [1-N- amino--hydroxy butyryl Kanamycin A] NH2 Ac NH2 Ac 4' 6' 4' 6' 5' O Ad HO 5' O Ad X HO 1' H HO 1' H 3' 2' HO 3' 2' OH X OH O 4 HN 2 3 2 O OH 4 H N Phos O 2 3 2 6 1 NH Phos HO C CH CH2 CH2 NH2 6 1 5    HO NH2 O 5 L-AHBA O 1'' HO 5'' O HO 6'' 1'' OH HO O 2'' OH H 2N Kanmycin A HO 3'' 4'' H 2N 2''  Semi-synthetic analog of Kanamycin A  produced by acylation of 1-amino group with L-AHBA [L--Amino-α-Hydroxy Butyric Acid].  Advantages: 1) Less toxic than Kanamycin or Gentamicin. 2) L-AHBA   binding to R-factor mediated enzymes  prevent adenylation at C4' & phosphorylation at C3'   potency & broaden spectrum.  Uses: serious bacterial infections that are resistant to other aminoglycosides. Preparation of Amikacin: O  NH2 *  O NH2 HO C CH CH2 CH2 KANAMYCIN N CH CH2 CH2.. OH L-AHBA H KANAMYCIN NH2 OH other amino groups are protected during synthesis  Tobramycin (Nebcin)® [Deoxy Kanamycin B] NH2 Ac 4' 6' NH2 5' O Ac Ad HO 4' 6' 5' 1' H O X Ad HO 3' 2' HO 1' H 4 HN 3' 2' NH2 O 2 3 2 OH 4 H N Phos O 2 3 2 6 1 NH Phos HO 2 6 1 NH2 5 HO 5 O O 1'' 5'' 1'' HO HO 6'' O O OH Kanmycin A HO OH HO 3'' 2'' 2'' 4'' H 2N H2N  Produced by fermentation of Streptomyces tenebrarius.  Lack 3'-OH  resist O-phosphorylation  broader spectrum > Kanamycin.  But, can be adenylated & acylated  inactivation.  Active ≠ most strains of Pseudomonas aeruginosa [> Gentamicin by 2-4 folds].  Sisomicin  Isolated from Micromonospora inyoensis.  Contain unsaturated amino sugar.  More potent > Gentamicin. Netilmicin  1-N-ethyl Sisomicin  Semi-synthetic analog   inhibition ≠ resistant bacteria.  Less toxic than sisomicin CH2 NH2 & gentamicin. O 4 H N H2N O 2 3 2 6 1 NH HO 2 NH Et 5 O 1'' [Netilmicin] O HO OH 2'' HN H3C CH3  Gentamicin [Garamycin®] NH CH3 H3C CH 6' Ac X 4' Ad 5' O 1' H X 3' 2' 4 HN NH 2 O 2 3 2 Phos 6 1 NH 2 HO 5 O Gentamicin C1 1'' O 3HC OH HN 2'' HO CH 3 Garosamine Suger: specific for all Gentamicins o Produced by fermentation of Micromonspora purpurea & other related soil m.o. [mixture of compounds] o Lack 3'-OH & 4'-OH  resist R-factor enzymes [broader spectrum], but inactivated at other sites. o Uses: Has significant activity ≠ Pseudomonas aeroginosa infections [in burns, pneumonias & UTI], also, prevent fouling of soft contact lenses. o Inactivate if put with β-lactam antibiotics in same preparation  N-acylation by β-lactam ring  inactivation of both COOH antibiotics. NH H2N RCOHN Sugar O RCOHN NH 2 O HO + N O O HN COOH Sugar O Sugar B-Lactam Antibiotic HO NH2 GenamicnC-2a Active Active O Sugar Inactive  Neomycin C NH2 Same as Kanamycin B [6-amino-6-deoxy glucosamine] HO O HO H2C NH2 NH2 H2N O O 4 HO OH HO O NH2 H2C 5 O OH NH2 O fourth ring [Pentose sugar] OH  Obtained from Streptomyces fradiae.  It's THE MOST TOXIC AMINOGLYCOSIDE  NOT taken systemically.  Uses: 1) Dermatological infections. 2) GIT infections. 3) Acute bacterial peritonitis, in hepatic coma, before surgical operations.  [III] Aminoglycosides with Spectinamine Spectinamycin Spectinamine Ring Spectinamine Ring CH3 OH O OH HN OH H3C O O NH CH3 O O NHCH3 O OH O OH OH O NH CH3 CH3  Produced by fermentation of Streptomyces spectabilis.  Composed of Spectinamine moiety + bicyclic moiety fused at 4- OH & 5-OH. [with only one sugar]. Uses:  Alternative to penicllinnot cause oto- or nephrotoxicity.  It's the drug of choice in treatment of GONORRHEA caused by penicillinase-producing N. gonorrhea. Macrolide The term macrolide = large lactone (cyclic ester) They have two characteristic sugars They are very water soluble They have narrow spectrum (but active against most gram positive bacteria) MOA: They interfere with protein synthesis by binding with 50s Therapeutic uses: Used for upper and lower respiratory tract infection Side effects  They are safe but may cause GIT complains  May cause hepatotoxicity 1) 14-mambered ring macrolide Erythromycin  Isolated from Streptomyces erythreus  One of the safest antibiotic in clinical use  Used topically for treatment of acne  Its acid instability is due to presence of ketone & two alcohol groups 2) 15-mambered ring macrolide Azithromycin (zithromax®)  Semisynthetic from erythromycin by insertion of N-CH3 between C9 & C10  Carbonyl group absent  more stable than erythromycin to acid Semi-synthetic analogs 1) Clarithromycin [Klacid,Biaxin] ®  Semi-synthetic drug from CH3 N - Me2 HO erythromycin by methylation of 6- O OH  etherification. CH3 CH3 O O CH3  6-OH involved in ketal formation HO CH3O 6 OH which form inactive drug + GIT CH3 CH3 cramps. C2H5 O O CH3 O CH3  Methylation of 6-OH O OH ADVANTAGES: CH3 OCH3 1) No cyclic ketal formation [inactivation + GIT cramps]. 2)  absorption & better blood level. 3)  lipophilicity   & less frequent dose for mild infections. 4)  gastric upset. 2) Azithromycin [Zithromax®]  It is a prototype of a series of nitrogen- containing 15-membered ring macrolides CH3 known as azalides. 9 8 N - Me2 CH3  Semi-synthetic  ring-expanded analog N 9a HO CH3 [15-membered] by insertion of N-methyl 10 CH3 O CH3 HO O HO between C9-C10 + removal of C=O. OH  Not form cyclic internal ketal. CH3 C2H5 CH3 O O CH3 O ADVANTAGES : CH3 O OH 1) No cyclic ketal formation [inactivation + GIT CH3 OCH3 cramps] 2) More acid stable. 3) With longer duration [once daily] 4) Greater G-ve activity >Erytho-& Clarithro N.B.: It has significant postantibiotic effect against a number of pathogens. Spiramycin (Rovamycin)  Spiramycin is a macrolide antibiotic produced by the growth of certain strains of Streptomyces ambofaciens.  used as erythromycin & also to treat protozoal infections and toxoplasmosis.  given orally, rectally or intravenously. Side effects of Macrolides  GIT problems.  Cholestatic jaundice: especially with Erythromycin Estolate [result from hypersensitivity reaction  bile becomes granular in bile duct   its flow  back up into circulation].  Ototoxicity: transient deafness [especially at  doses].  Erythromycin  level of anti-coagulants, anti-diabetetics, carbamazepine  By inhibition of liver microsomal enzymes.  Not used for patients with hepatic dysfunction  drug accumulation in liver.