Antibacterial Flashcards
Gram positive
Simple cell wall with 50% peptidoglycan which is bound directly to cytoplasmic membrane
Gram negative
Outer membrane made of lipid bilayer, over peptidoglycan membrane, greater diffusion barrier.
Antibiotic definition
Natural substances which is made by a micro-organism and prevents/kills the growth of another
Bactericidal
Kills organisms, decrease population size
Bacteriostatic
Inhibits growth, lesser decrease in population size but no increase.
Selective Toxicity
Prevent action on non-pathogenic human microbiome and adverse side effects
Benefits of combination therapy
Less resistance, increase efficacy and synergism, broader spectrum.
Drugs which target protein synthesis
Mupirocin (pre-ribosomal stage inhibition). Oxazolidinones, Tetracyclines, Aminoglycosides, Chloramphenicol, Macrolides (Ribosomal inhibitors) and Fusidic Acid
Selective Toxicity of protein synthesis targeting antibacterials
Ribosomal size is different between mammals and bacteria. Enzyme which Mupirocin acts on is different and lower affinity for mammal one, Uptake of tetracyclines and fusidic acid is not as good in mammalian cells. Can get ADR from interaction with mitochondrial synthesis
Mupirocin mode of action
Competitive inhibitor for isoleucyl tRNA synthetase, enzyme which links tRNA amino acids together. No raw materials to create polypeptide chain at ribosomes. Bacteriostatic
Clinical Use of Mupirocin
Only topical as rapidly hydrolysed when ingested. Only against Gram positive. Staphylococcal or streptococcal skin infections, stop nasal carriage of MRSA in hospital patients & staff.
Oxazolidinones
Bind to 50S subunit and prevent correct positioning of aminoacyl-tRNA and blocks entry of subsequent molecules. Bacteriostatic
Examples of Oxazolidinoes
Linezolid or Tedizolid (more recent, less ADR and mylosuppression, more ABx activity). All are fully synthetic
Clinical use of Oxazolidinones
Gram positive only, unable to get high intracellular cones of gram negative. Skin and soft tissue infections and Hospital acquired pneumonia. IV ORAL
ADR of oxazolidinoes
Reversible thrombocytopenia and anaemia from myelosuppression. Mild LFT abnormalities
Tetracycline action
Bind to 30S subunit via hydrogen bonds. Prevents associated of aminoacyl- tRNA with the ribosome. Lipophilic tetracyclines more active than hydrophilic.
Clinical use of tetracyclines
broad spec, Oral, IV or topical.Chlamydia, mycoplasma pneumonia, cholera, Lyme disease,
Rocky Mountain spotted fever
Examples of tetracyclines
New = tigecyclin IV only. Doxycycline, tetracycline
ADR of tetracyclines
Due to ability to chelate metal ions CI in young children and late-pregnant woman and deposits in bone and teeth. Photosensitivity.
Aminoglycosides action
Bactericidal. Bind to 30S or both subunits mRNA misreading causes abnormal proteins to be synthesised. Hydrophobic regions burrow into membrane, destabilising it and contents leak/lyse.
Clinical use of aminoglycosides
IM or IV. Montherapy in severe sepsis (particular causative agents), plague, enterococcal endocarditis. Combo therapy for gram positive TB or anaerobic infections
Examples of aminoglycosides
Polycationic with 2 sugars enclosing 3rd ring structure. streptomycin, gentamicin, neomycin.
ADR of aminoglycosides
Not great selective toxicity. Ototoxicity, Nephrotoxicity, Neuromuscular blockade.
Chloramphenicol Action
Binds to 50S subunit and inhibits the enzyme responsible for amino acid chain elongation - peptidyl transferase.
Chlorampenicol clinical aspects
BROAD-SPEC bu toxicity restricts use. Oral, IV or topical. Typhoid and paratyphoid due to Salmonella infections
ADR of chlorampenicol
Myelosuppression and Gray Syndrome (in the very young - life threatening)
Macrolides Action
Blocks the exit of the polypeptide chain from the ribosome by binding to 23S rRNA on 50S subunit. Leads to premature dissociation of the chain from peptidyl transferase and incomplete proteins formed
Macrolide examples
Lactone ring with 2 sugars and one amino sugar attach. e.g. Azithromycin or erythromycin
Macrolide clinical use
Chlamydia, pneumonia, syphilis, Corynebacterium diphtheria, Legionnaires’ disease
Fusidic acid action
Binds to elongation factor G in post-translocation state, can’t dissociate from chain, no further protein synthesis can occur. EFG is responsible for the translocation movement of mRNA and tRNA along chain.
Clinical aspects of fusidic acid
natural, only gram positive action, topical IV and oral. rare ADR. Staphylococcal infections or in combo therapy to stop resistance of EFG mutations
Peptidoglycan synthesis
movement from cytoplasm to membrane then to outside of membrane to be incorporated. Outside membrane: Transglycosylation (disaccharide incorporated) and Transpeptidation (cross link 3rd-4th amino acids of chains) via d-alanine energy
Enzyme for peptidoglycan synthesis
PENICILLIN BINDING PROTEIN. 2-domains, bi-functional, membrane associated. beta-lactams bind to enzyme. glycopeptides bind to substrate
beta-lactam examples
Parents compound = penicillin, all have lactam ring structure. Penicillin, cephalosporins, carbapenems and monobactams. Benzylpenicillin, broad spec = amoxicillin, penicillinase resistant = flucloxacillin
Mode of action of beta-lactams
Competitively inhibit PBP, bind via serine residues in active site during TRANSPEPTIDATION reaction as structure analogous to d-alanine d-alanine dipeptide. Null-reaction can occur, no cross-linking, little rigidity in cell wall, cell bursts. Enzymes degrading old cell wall still act to weaken wall further.
Clinical aspects of beta-lactam use
Broadspec activity. Can have allergy to metabolite of drug Pneumococcal pneumonia, syphilis, gonorrhoea.
Beta-lactam resistance
Beta-lactamases can hydrolyse ring structure of ABx. A, B and C serine beta-lactamase nucleophilic attack create open ring structure. D = zinc beta-lactamase.
Prevent resistance of beta-lactams
Clavulanic acid. Is a beta-lactam with no ABx properties. Binds to beta-lactamases instead of active drug and prevents breakdown and inactivity. e.g. co-amoxiclav
Example of gylcopeptides
Vancomycin
Mode of action of glycopeptides
Steric hinderance of transglycosylation. H bond to d-alanine d-alanine substrate for PBP. Minor effect on transpeptidation by preventing cross-link.
Clinical use of glyopeptides
Gram positive only. IV/IM unless for GI C.difficle infection (oral). Use in MRSA esp penicillin allergic patients. C.difficle colitis. In combo with aminoglycosides for enterococcal endocarditis.
ADR of glycopeptides
Red Man syndrome when given too quickly. Ototoxicity, and nephrotoxicity. reversible thrombocytopenia and neutropenia.
Polymyxins action
Polymyxin B and polymyxin E. Aggregate with both cytoplasmic membrane and outer membrane, compromise integrity and function.
Polymyxins clinical use
Mostly gram negative action. Highly neuro and nephro toxic. use in Pseudomonas (CF), gut decontamination, burn infections and drug resistant gram negative pathogens. Aersol (CF patient use), IV, oral, topical, IM
Daptomycin
Aggregates and depolarises cell membrane, compromising integrity and structure. Action mediated by calcium ions. Only Gram positive action. IV. use on skin and soft tissue infections.. ADR include muscle toxicity which is rare.
Drugs inhibiting nucleotide biosynthesis and how they are selectively toxic
Trimethoprim and sulphonamides (e.g. prontosil, sulfasalazine). Mixture = co-trimoxazole. Act on tetrahydrofolate synthesis. Mammals get folate from diet, no need for synthesis reaction so no enzymes in mammal cell
Drugs inhibiting bacterial DNA topoisimerase
Quinilones and fluoroquinilones
DNA damaging antibacterials
Nitroimidazoles
Drugs inhibiting RNA synthesis
Rifamycin
Sulphonamides Action
Competitive inhibition of dihydropteroate synthetase. Analogous structure to normal substrate PABA which gives product of dihydropteroate. ABx gives null product unable to form tetrahydrofolate.
Sulphonamides ADR
hepatitis, allergic reaction, myelosppression and AKI = interstitial nephritis and crystalluria
Mode of action of trimethoprim
Competitive inhibitor of dihydrofolate reductase, enzyme which creates tetrafolate from dihydrofolate.
Use of co-trimoxazole
UTI, RTI, GI infection but use restricted due to resistance potential. Combinations used for treatment/ prophylaxis of Pneumocystis jiroveci pneumonia in HIV.
Mode of action of quinolines and fluoroquinilones
Inhibit the action of DNA gyrase/topoisomerase2 (negative supercoiling for packing) and DNA topoisomerase IV (decatenation). Enzymes covalently link to DNA via tyrosine residue on enzyme and 5” strand, lead to ATP dependent strand breaking and repair. ABx binds to quinolone binding pocket structure in broken DNA at 5” end, via base-stacking. Trap DNA in broken state prevent resealing. Bactericidal
Use of quinolones and fluoroquinolones
gram -ve = gyrase primary target. gram +ve = toposiomerase primary target. Bacteriocidal. Gonorrhea, GI infections, anthrax, UTI and RTI.
Selective toxicity of quinolones
Gyrase not present and topoisomerase II is a A2 dimer, not A2B2 like bacterial cells.
Examples of quinolones and fluoroquinolones
Nalidixic acid, Ciprofloxacin, Levofloxacin (1-3 gens) Increase gen, increase spec of activity, increase toxicity.
ADR of quinolones and fluorquinolones
Rarely - tendonitis, GI upset, phytotoxicity, CNS toxicity. CI in the pregancy and adolescents due to arthropathy.
Selective toxicity of nitroimidazoles
Ingested as prodrug, only enzyme in anaerobic bacteria activate them. Nitro group of drug is reduced by low-redox- potential nitroreductases e.g. Pyruvate: ferredoxin oxidoreductase (PFOR). No anaerobic enzymes in humans
Mode of action of nitroimidazoles
DNA damage by oxidation, strand break and helix destabilisation
Use of nitroimidazoles
Obligate anaerobic bacteria and protozoa, facultative anaerobes if in anaerobic condition. RTI, abode infections, meningitis, brain abscess, osteomyelitis, oral and dental infections, C.difficile colitis, H.pyloria gastoduodenal ulcers.
ADR of nitroimidazole
GI disturbance, CNS effect, reversible neutropenia. With alcohol accumulation of acetaldehyde give hangover feeling, vague animal evidence of teratogenic, carcinogenic and mutagenic.
Examples of rifamycins
Rifampicin, rifamycin. Natural antibiotic
Mode of action of rifamycins
Bind to beta-subunit of RNA polymerase of bacteria. Block exit channel of chain. Leads to abortive initiation and RNA strand breaks off. Baceriocidal.
Use of rifamycins
TB therapy, Leprosy, S.aureus combo therapy with fusidic acid, penicillin resistant S.pneumoniae. little gram negative activity
ADR of rifamycins
Heptatis, skin reaction, flu-like reaction, urine discolouration in oral dose
