1Dolly MehtaDolly [email protected] TherapyCell Wall Cell memb Protein syn Nucleic acid syn 22Bacterial Cell Wall ComponentsPeptidoglycanMN acetylmuramic acid (NAMA) GN acetylglucosamine (NAG)Penta peptide Glycine 3M G M G M GM G M G M GM G M G M GM43Proteoglycan (PG) (15-50 nm thick)MbGram +Membrane(LPS)Lipopolysacharides Gram -PG (2 nm thick)Membraneand proteinsperiplasm564Biosynthesis of Peptidoglycan30 enzymes1) Precursor formation: CytoplasmThree stages: 1) Precursor formation: Cytoplasm2) Binding with phospho-C55 lipid carrier to form long polymer: Cell membrane 3) Cross-linking in cell wall7MUDPUDPMCYTOhL-alanineD-alanineracemaseP-C55 lipidP-P-C55MUMPGUDPUDPP-P-C55MGMEMBP-P-C55MGsynthetaseMEMBWALLGMM G M G M GP-P-C55 lipidtransglycolaseP8transpeptidaseG5β-Lactam antibioticsPenicillin G and VNafcillinAmpicillinAmpicillinExtended-spectrum penicillinCephalosporinsClavulanateCarbapenems9Penicillin: β-Lactam antibioticsDrug of choice for a large number of diseasesDiscovered by Alexander Flemming 1928. Produced by penicillium106CCHCOOHCH3CH3SCHNCHC=ONHCR=OBA2CHCOOHNC=O1AB β-lactum ringThiazolidine ring1 penicillnaseR decides:Penicillin subtype1 penicillnase2 amidasestability for stomach acidsAntibacterial activityresistance to β-lactamase11Mechanism:Inhibits cross linking of peptidoglycan (transpeptidase)M G M G M GM G M G M GM G M G M GM127β-lactum moeity of penicillins binds covalently (irreversibly) with penicillin-binding proteins (PBPs) at serine residuePBPPBPβ-lactamase13β-lactum antibodiesAcylation of PBPsI hibiti f PBPCell lysisInhibition of PBPs Structural irregularities148PBPs:belong to the family of acyl serine transferaseshigh-molecular-weight (HMW) PBPslow-molecular-weight (LMW) PBPsß-lactamases 15PBPsHMW169LMW17Class A-Bβ-lactamase1810PBP’s (40kD-91kD):Number of PBPs varies within bacterial strain. i.e. S aureus has 4 PBPs whereas E coli has 7Apparent Binding of Proteinppmolecular weightgpenicillin( % total )Molecules/cell1 91000 8.1 2302 66000 0.7 203 60000 1.9 504 49000 4.0 1105 42000 64.7 18006 40000 20.6 57019Affinity of PBPs to antibiotics is variablePenicillin (lytic as well as non-lytic)Lytic PBP1; Non-lytic (PBP2/3) (affect holin-like proteins in bacterial cell memb which alter membrane potential)2011Mechanisms of Resistance:A. Elaboration of altered PBPsa) decreased affinity for β-lactamsa2. by transposans from unknown orga1. formed by homologous recombination between PBPs of different bact sp.b) structural differences in PBPsb) structural differences in PBPs21B. Inability of agent to penetrate to site of actionb1. Gram (-) bact outer layer of LPSSmall hydrophilic antibiotics can pass through channels porinsi.e. amoxicillin, ampicillin>Penicillin GP aeruginosa resistant to most antibiotics lacks porins2212C. Increased expression of efflux pumps i.e E. coli23D. Production of β-lactamased1.β-lactamases class A-D:Hydrolyse β lactam ring of penicillin's d1. βlactamases class AD:Class A (extended spectrum β-lactamase): degrade penicillin, some cephalosporin's and carbapenemsClass B (Zn-dependent): destroy all β-lactums except aztreonamClass C: cephalosporin'sClass D: cloxacillin2413Gram (+), β lactamase is secreted extracellularly in large amtsd2. Site of liberationGram (-), β lactamase is located in the periplasmic space, small amounts. Primary mechanism of acquired resistance!d3. Other factors: surviving bacterial cell, biofilms produce bacteria in prosthetics252614Classification Spectrum Natural PenicillinsPenicillin V and G (phenoxymethyl penicillin)Gram (+) cocci, hydrolyzed by penicillinase so ineffective against most strains of S. aureusβ-lacatamse resistant Penicillin; methicillin(discontinued in US),Less active agnst bacteria sensitive to Penicillin G First choice for Saureusand SepidermidisOCH2-CH2-OCH3 (discontinued in US), nafcillin, isoxazoylpenicillinFirst choice for S aureusand S epidermidisAminopenicillins (or modern spectrum) Ampicillin, amoxicillinGram (-) e.g Hemophillus influenzae, E.Coli, Neissaria sp.Administered with b-lactamse inhibitor such as clavanate to prevent hydrolysisCarboxypenicillinCabbenicillinGram (-) e.g. pseudomonas sp, enterobacter sp.Inferior to ampicillin GOCH3 CH2-R1NH2(discontinued in US)Ticarcillinagainst Gram + cocciUreidopenicillins(extended penicillin) Mezlocillin, Azliocillin (discontinued in US), PiperacillinPseudomonas sp, 10 times more effective than carboxypenicillinCH-COOR27Distributionwidely distributed throughout body fluids but conc varies in diff tissues. Ætherapeutic concentrationsis achieved readily inGeneral features of the PenicillinsÆtherapeutic concentrationsis achieved readily in tissues and in secretions such as joint fluid, pleural fluid, pericardial fluid, and bile ÆDo not penetrate phagocytic cells, very low conc in prostatic fluids, brain tissue, and intracular fluidÆ<1% in CSF when meninges are normal; ~5% when inflamed meningisg28Active transport process pumps penicillin's from CSF to the bloodstream. This mechanism is blocked by Probenecid15ExcretionPredominantly eliminated rapidly by glomerular filtration. Short half life (30-90 min) in body. So higher urine concentrations. 29Specific AgentsPenicillin G Low acid stability; gastric juices at pH<2 degrades it rapidlFoodPenicillin V StabilityMore acid stableit rapidly.Food interference (30 min before meal) Absorption Yield 2-5 fold more plasma level than GOral dose: Rapidly absorbed and max conc 30-60 min in blood; should be used only30Peak value 0.3ug/ml after an oral dose of 250 mg in adultlevel than GPeak value 3ug/ml after an oral dose of 500 mg in adultblood; should be used only when proven efficacious16Parenteral administration of Penicillin G peak conc in plasma reached within 15-30 minbut decline due to 30 min half lifeRepository Forms of Penicillin G:Penicillin G procaine (Wycillin) (benzyl penicillin with local anasethetic agent procaine)slowly absorbed after IM injection but an injection of 300,000 units will maintain adequate plasma levels for 24 hours. ÆSyphillisRTI anthraxÆSyphillis, RTI, anthraxPenicillin G benzathine (Bicillin L-A, Permapen) has the slowest rate of absorption even after IM absorbtion. An injection of 1.2 million units will maintain adequate plasma levels for 10 days.31Distribution0.35L/kg60% is reversibly bound with albuminsignificant amount appear in liver bilesignificant amount appear in liver, bile, kidney, semen, lymph, intestineExcretionPen G
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