1Dolly [email protected] TherapyCell Wall Cell memb Protein syn Nucleic acid syn2Bacterial Cell Wall ComponentsPeptidoglycanMN acetylmuramic acid (NAMA)GN acetylglucosamine (NAG)Penta peptide Glycine M G M G M GM G M G M GM G M G M GM3Proteoglycan (PG) (15-50 nm thick)MembraneGram +PG (2 nm thick)MembraneLipopolysachrides and proteinsperiplasmGram -Biosynthesis of Peptidoglycan30 enzymesMUDPUDPMP-C55 lipidP-P-C55MUMPGUDPUDPP-P-C55MGCYTOMEMBWALLP-P-C55MGGMM G M G M GP-P-C55 lipidtranspeptidaseP4I. structural analog of D-Ala (competitive inhibitor) III. Therapeutic Use: Effective agnst M. tuberculosisused WHEN PRIMARY Anti-Tuberculosis agents(such as Isoniazid, rifampin) failedCycloserine (Seromycin)II. Mechanism:MUDPcycloserineII. stable in alkaline solution rapidly destroyed in neutral or acid pHIV. Absorption, Distribution and excretionOrally absorbed 70-90%distributed throughout body fluids (CSF conc. = plasma)Metabolism slow, only 50% excreted UNCHANGEDin urine in Ist 12 hrs renal patients: accumulate to toxic conc, removed by dialysisV. Untoward EffectsCNS: headache, tremor, confusion etcCONTRAINDICATED: Epileptic patientsCaution: patients with history of depression or suicidal attempts5VancomycinIII. Antibacterial activity: Gram (+), However, Gram(–) are resistant because D-ala-D-ala target to D-ala-D-ser or D-ala-D-lactateI. Tricyclic glycopeptide antibioticII. Mechanism: Inhibits polymerization P-P-C55MGMGP-P-C55MG()n+MG()nIV. Absorption, Distribution and excretion: Oral absorption poor; slow IV is preferred, NEVER IMappears in body fluids and CSF90% excreted by glomerular filtration V. Untoward Effects:Hypersensitive Reacn(skin rashes, and anaphylaxis, Chills, rash)Rapid administration causes flushing, tachycardia, hypotension, erythematous or urticarial reac cause “red-neck” or “red-man” syndrome bydirectly inducing toxicity in mast cells6III. Antibacterial Activity: Gram (+) cocci and bacilli. However, bact strain such as Enterobacteriaceae, Pseudomonas, Candida spp and Nocardia are resistant IV. Use: Restricted to topical use such as for skin and eye infections BacitracinII. Mechanism:P-P-C55 lipid P-C55 lipidPenicillin: β-Lactam antibioticsDrug of choice for a large number of diseasesDiscovered by Alexander Flemming 1928. Produced by penicillium7CCH COOHCH3CH3SCHNCHC=ONHCR=OBA12AB β-lactum ringThiazolidine ring1 penicillnase2 amidaseR decides:stability for stomach acidsAntibacterial activityPenicillin subtyperesistance to β-lactamaseII. Mechanism:M G M G M GM G M G M GM G M G M GMa. Inhibits cross linking of peptidoglycan8b. binds covalently with penicillin-binding proteins (PBPs). PBPPBP1. Several subtypes: PBP1, PBP2, PBP32. Number of PBPs varies within bacterial strain. i.e. S aureus has 4 PBPs whereas E coli has 73. Affinity of PBPs to antibiotics is variableii Structural irregularities i. Inhibition of transpeptidaseCell lysis Lytic (PBP1)PBP’s:Penicillin (lytic as well as non-lytic)Non-lytic (PBP2/3) (affect holin-like proteins in bacterial cell membwhich alter membrane potential)9III. Mechanisms 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. 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 Abts as lacks porins10C. Increased expression of efflux pumps i.e E. coliD. Production of β-lactamase:d1. β-lactamases class A-D:Class A: degrade penicillin, some cephalosporin's, Class B: destroy all Antibiotics except aztreonamClass C: cephalosporin'sClass D: cloxacillinHydrolyse β lactam ring of penicillin's11Gram (+), β lactamase is secreted extracellularly in large amtsGram (-), β lactamase is located in the periplasmic space, small amounts. Primary mechanism of acquired resistance!d2. site of liberation12Gram (-) e.g. pseudomonas sp, enterobacter sp.Inferior to ampicillin against Gram + cocciCarboxypenicillinCabbenicillinticarcillinGram (+) cocci, hydrolyzed by penicillinase so ineffective against most strains of S. aureusNatural PenicillinsPenicillin V and G (phenoxymethyl penicillin)Pseudomonas sp, 10 times more effective than carboxypenicillinUreidopenicillins(extended penicillin) Mezlocillin, Azliocillin(discontinued in US), PiperacillinFirst choice for S aureus and S epidermidisβ-lacatamse resistant Penicillin; methicillin(discontinued in US), nafcillin, isoxazoylpenicillinGram (-) e.g Hemophillus influenzae, E.Coli, Neissaria sp.Aminopenicillins (or modern spectrum) Ampicillin, amoxicillinSpectrum ClassificationOCH2-CH2-OCH3 OCH3 CH2-R1NH2CH-COORSpecific AgentsPenicillin G Low acid stability. Degraded by gastric juicesRapid absorbed orally (within 30-60 min in blood)Food interference (30 min before meal) Peak value 0.3mg/ml after an oral dose of 250 mg in adultPenicillin V More acid stableYield 2-5 fold more plasma level than GPeak value 3mg/ml after an oral dose of 500 mg in adult13Parenteral administration of Penicillin G peak conc in plasma reached within 15-30 minbut decline due to 30 min half lifeRepository Forms of Penicillin G:i. Penicillin G procaine (Wycillin) slowly absorbed after IM injection but an injection of 300,000 units will maintain adequate plasma levels for 24 hours. ii. Penicillin G benzathine (Bicillin) 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.Distributionwidely distributed throughout body fluids but concvaries in diff tissue Apparent volume of distribution is 0.35L/kg60% of Penicillin G is bound with albumindo not achieve high levels in the CSF when meninges are normal. Active transport process pumps penicillin's from CSF to the bloodstream. This mechanism is blocked by Probenecid.meningitis, inflammation induced increase in the permeability leads to high levels of penicillin14Excretion1. Predominantly eliminated unchanged via the glomerular filtration (10%) and tubular secretion (90%). 2. Clearance Is lower in neonates and infants (3hrs in 1wk old baby)3. Active secretion can be blocked by probenecid.4. Renal dysfunction, hepatitis, anuria increases the half life of GTherapeutic usesPenicillin G and V: Pneumococcal infections, Pneumonia,Steptococcal infections,