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MPHM14 Antibacterial Chemotherapy OSPAP Programme

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MPHM14 Antibacterial Chemotherapy OSPAP Programme WEEK 27 OSPAP Programme MPHM14 Antibacterial Chemotherapy Slide 1 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Overview • Agents targeting the cytoplasm – [Sulfonamides] – Trimethoprim – Nitrofurantoin • Agents targeting the ribosomes – Chloramphenicol – Linezolid – Tetracyclines – Macrolides – Aminoglycosides • Agents targeting the nuclear material – Rifamycins – Fluoroquinolones • Updates and new developments • Clinical applications Slide 2 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 The Bacterial Cell ( Prokaryotic ) SULPHONAMIDES TRIMETHOPRIM NITROFURANTOIN http://whyfiles.org/126dna_forensic/images/dna.gif Slide 3 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Agents acting in the cytoplasm • Many common biochemical processes in cytoplasm of all cells • Rely on differences between prokaryotic and eukaryotic cells for selectivity – Agents targeting metabolic processes only found in bacteria provide selective antibacterials • Bacteria synthesise several vitamins, e.g. folic acid, not synthesized in mammalian cells – These processes are good targets for antibacterial agents • The sulfonamides are antifolates (like methotrexate) and interfere with the bacterial biosynthesis of folic acid • Trimethoprim is also an antifolate, targeting a different part of the folic acid biosynthetic pathway • Nitrofurantoin acts on several processes in the cytoplasm, some similar to mammalian processes, but… – Is prodrug and only activated efficiently in bacterial cells Slide 4 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Sulfonamide Antibacterials • Sulfonamides were the first synthetic antibacterials used clinically • Bacteriostatic action • Sulfonamides are structural mimetics of para -aminobenzoic acid (PABA, essential metabolite) and compete for a key enzyme in the synthesis of folic acid • Folic acid is an essential metabolite for mammals (cannot be synthesised by mammalian cells), so this interference in folic acid synthesis is the basis of the selectivity of the sulfonamides • Sulfonamides are extremely rarely used now due to extensive resistance in both G+ve and G-ve bacteria – Alterations to the enzyme target, dihydropteroate synthase (DHPS) – Mutations to gene for DHPS resulting in poor sulfonamide binding • Only sulfamethoxazole (as Co-trimoxazole) and sulfadiazine in BNF Slide 5 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Folic Acid Synthesis PABA Folic acid Dihydropteroic acid NH 2 Sulfonamides resemble PABA and are mistakenly used instead, preventing synthesis of folic acid H2NO 2S Slide 6 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 NH2 OMe Trimethoprim N H2N N OMe OMe • Trimethoprim is an antifolate agent through dihydrofolate reductase (DHFR) inhibition; bacteriostatic • Used for UTIs (good renal excretion as unchanged drug), acute and chronic bronchitis (well distributed), pneumocystis pneumonia • Can be used as monotherapy or in combination (synergistic) with sulfamethoxazole (Co-trimoxazole) in ratio 5 : 1 – Similar pharmacokinetics gives best combination • Co-trimoxazole acts on two enzymes in the same biosynthetic sequence (sequential blocking ) • Doses of both drugs are lower than would be required if either used alone so side-effects (and possibly resistance) can be minimised Slide 7 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Co-trimoxazole (Septrin) NH2 CO2H OH OH N HO2C N N OPP N N H Dihydropteroate H2N N N synthetase (DHPS) H2N N N L-Glu O H CO H Sulfamethoxazole 2 OH N CH CH CO H H 2 2 2 Although reduction of DHF to THF also occurs N N N in mammalian cells, trimethoprim has about H 40,000x greater affinity for the bacterial H2N N N enzyme than the mammalian version – hence FOLIC ACID the selectivity NADPH O H CO H O H 2 NADP CO2H OH N CH2CH2CO2H OH N CH CH CO H H H H 2 2 2 N N N N NADP NADPH N N H H Dihydrofolate reductase H2N N N H N N N H (DHFR) 2 H TETRAHYDROFOLIC ACID DIHYDROFOLIC ACID Trimethoprim Slide 8 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 UTIs • Although sulfonamides rarely used now, co-trimoxazole is sometimes still useful for urinary tract infections – Susceptibility should be established 1 st [culture / MS methods] • Also useful for: – Pneumonia due to Pneumocystis jirovecii (fungus, was called Pneumocystis carinii ) – Toxoplasmosis and nocardiasis • Co-trimoxazole associated with rare, serious ADRs, especially in elderly patients – Was replaced by amoxicillin or cephalexin, but less commonly used now due to resistance (amoxicillin) and increased risk of C. diff infection after use (cephalexin) • Nitrofurantoin more commonly used now – (Relatively) broad spectrum, bactericidal agent, particularly against E. coli , most Enterococci , Klebsiella sp., Staphylococci and Streptococci (But poor activity vs Proteus sp. and inactive vs Pseudomonas sp.) – Rapid renal elimination after oral admin: low serum, high urinary concentration Slide 9 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Nitrofurantoin MoA • Activated by several bacterial enzymes to reactive nitrosyl radical • Reacts with cytoplasmic proteins and other macromolecules • Inhibits: protein synthesis, aerobic (carbohydrate) energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis • Resistance rare, even although introduced into clinic in 1952; resistance may be due to non-specific activity – resistance would require concurrent changes to many enzymes, proteins and pathways = unlikely • Although broad spectrum, rapid and efficient absorption from GI tract reduces risk to GI bacteria (low risk of C. diff resulting) Nitrosyl radical Slide 10 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 The Bacterial Cell ( Prokaryotic ) CHLORAMPHENICOL TETRACYCLINES MACROLIDES AMINOGLYCOSIDES LINEZOLID http://whyfiles.org/126dna_forensic/images/dna.gif Slide 11 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Agents targeting protein synthesis via ribosome Slide 12 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Transcription and translation Transcription and translation describe the processes by which the genetic code on DNA is converted into proteins In bacteria, these Replication processes all take place in Translation the cytoplasm, making an DNA Transfer RNA (tRNA) – amino acid easy target for antibacterial agents Transcription Selectivity is possible, as bacterial ribosomes are Messenger RNA (mRNA) RIBOSOME (rRNA) different to mammalian ribosomes Protein http://highered.mcgraw- hill.com/olcweb/cgi/pluginpop.cgi?it=swf::535::535::/sites/dl/free/0072437316/120077/micro06.swf::Protein%20Synthesis Slide 13 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Transcription and translation - revision TRANSCRIPTION • Genetic code on DNA template transcribed into messenger RNA by RNA polymerase • In bacteria, mRNA moves to ribosomes [ cf in eukaryotes, mRNA exits nucleus into cytoplasm] TRANSLATION • Ribosomes have two subunits: 30S and 50S in bacteria [70S] (40S and 60S in eukaryotic cells [80S]) • mRNA binds to small subunit of ribosome, followed by initiator: tRNA-methionine • Large ribosome subunit binds to small subunit. Large ribosome subunit has two binding sites, P and A in the peptidyl transferase centre (PTC) • Transfer RNAs carry amino acids to the ribosome site where mRNA binds (charged tRNA) • Only tRNA with codon of complementary sequence to that on mRNA can bind to ribosome Codon = 3 nucleotides (triplet), which codes for a specific amino acid • Ribosome moves along mRNA from 5′ to 3’: once peptide bond formed, non-acylated tRNA leaves P site and peptide-tRNA moves from the A to the P site A new charged tRNA-amino acid (as specified by the mRNA codon) enters A site • Peptide chain grows as amino acids added until stop codon reached, then leaves ribosome through protein exit tunnel Slide 14 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Chloramphenicol (Chloromycetin, Cm) • Originally obtained from Streptomyces venezuelae , now prepared synthetically HO H • Bacteriostatic with broad spectrum of activity; CH 2OH only R,R -isomer is active HN H O2N • Highly lipophilic and penetrates most tissues CHCl O 2 (crosses blood-brain barrier) • Active against Neisseria meningitidis , Streptococcus pneumoniae and Haemophilus influenzae (causes of meningitis) • Can be used in treatment of meningitis in patients with β-lactam allergies and drug of choice against typhoid fever • But…. severe toxicity possible, so only given systemically in life-threatening infections: benefit must outweigh risks • Side-effects after systemic admin include aplastic anaemia (bone marrow cannot replenish blood cells) – unpredictable and may occur weeks after treatment ceases • Commonly used topically in treatment of bacterial conjunctivitis Slide 15 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Chloramphenicol: MoA & resistance • Chloramphenicol binds to large ribosome subunit (50S) at the peptidyl transferase centre A site, preventing binding of the next charged tRNA • www.youtube.com/watch?v=0VINqUF-r5I • Binding involves 4 H-bonds from chloramphenicol to the ribosome and coordination to a Mg 2+ ion in the catalytic site • Selectivity arises due to differences between the conformations of bacterial and eukaryotic PTC • Chloramphenicol inhibits bacterial protein synthesis as it only binds to A site of bacterial ribosome • However, use of systemic chloramphenicol can lead to serious side effects due to inhibition of mammalian mitochondrial protein synthesis Slide 16 of 75 OSPAPMPHM14 Antineoplastic Chemotherapy WEEK 27 Resistance to chloramphenicol
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