Mechanism and Action of Antibiotics Flashcards
What are the main principles of antibiotic use?
- they target processes that humans do not possess (eg. bacterial cell wall)
- target processes that humans possess but bacterial versions are sufficiently different
- selective toxicity: antibiotics have greater toxicity to bacteria than human
What are the antibiotics that are active against the cell membrane?
- beta-lactam and cephalosporin
- glycopeptide
- cyclic peptide
- phosphonic acids
- lipopeptides
What are the targets, mechanisms and examples of beta-lactam and cephalosporin?
- target: penicillin binding proteins
- mechanism: prevent peptidoglycan cross-linking
Examples:
- penicillin G
- flucloxacillin
- tazobactam
What are the targets, mechanisms and examples of glycopeptides?
- target: C-terminal D-Ala-D-Ala
- mechanism: prevents transglycolation and transpeptidation (blocks addition of new peptidoglycan building blocks)
Examples:
- vancomycin
- teicoplanin
What are the targets, mechanisms and examples of cyclic peptides?
- target: C 55-isopropyl pyrophosphate
- mechanism: prevents carriage of building-blocks of peptidoglycan bacterial cell wall outside of the inner membrane
Examples:
- bacitracin
- polymyxin
What are the targets, mechanisms and examples of phosphonic acids?
- target: murA protein
- mechanism: inhibits first stage of peptidoglycan synthesis
- example: fosphomycin
What are the targets, mechanisms and examples of lipopeptides?
- target: cell wall stress stimulon
- mechanism: calcium dependent membrane depolarisation
- example: daptomycin
What are the 3 main classes of bacterial cell wall inhibitors?
- beta-lactams (penicillins and cephalosporins)
- vancomycin
- bacitracin
What effect does inhibiting cell wall synthesis have?
- normally leads to death of bacteria
- imbalance in cell wall architecture triggers bacterial autolysins that kill cell
What are the 3 types of bacteria that penicillins G and V attack (with examples)?
- gram positive and gram negative cocci:
- staphylococcus (infections of wounds)
- streptococcus - haemolytic (septic infections)
- enterococcus (endocarditis)
- pneumococcus
- neisseria gonorrhoeae
- neisseria menigitidis
- gram positive rods:
- clostridium (tetanus, gangrene)
- spirochaetes:
- treponema (syphilis)
- actinomyces (abcesses)
What are examples of B-lactamase-resistant penicillans and the spectrum of bacteria is covers?
- methicillin
- oxacillin
- naficillin
- covers same spectrum as penicillins G and V
What are examples of broad-spectrum penicillins and the spectrum of bacteria it covers?
- ampicillin
- amoxicillin
- covers same spectrum as penicillins G and V
- covers B-lactamase-free strains of:
- H. influenzae
- N. Gonorrhoeae
- E. Coli
- salmonella
- morasella catarrhalis (sinusitis)
What are examples of extended-spectrum penicillins and the spectrum of bacteria it covers?
- carbenicillin
- ticaracillin
- azlocillin
- piperacillin
- covers same as broad-spectrum
- plus pseudomonas aeruginosa
What are carbapenems and their features?
- broader anti-bacterial spectrum than B-lactase
- generally resistant to typical beta-lactamases
- bind PBPs permanently acylating them (penicillin binding proteins)
- poorly active against MRSA
- not active against bacteria with no cell wall
What is the role of PBPs?
involved in final synthesis of bacterial cell wall
What are the 3 mechanisms of bacterial resistance to B-lactam antibiotics with examples?
- bacteria produces B-lactamase which destructs antibiotic (eg. S. aureus)
- failure to reach target enzyme, gram negative organism changes outer membrane porins and polysaccharide components (eg. pseudomonas)
- failure to bind to the transpeptidase (eg. S.pneumoniae)
What are the 4 classes of B-lactamases and their mechanisms of action?
- A, B, C and D
- ACD uses serine to hydrolyse
- B uses zinc ions to hydrolyse
What is the use of B-lactamase inhibtors?
can be used with B-lactam antibiotic as an alternaltive to B-lactamase-resistant antibiotcs
What are cephalosporins with examples, the infections they treat and the possible complication
- alternative to penicillins
- classified by generations (1st, 2nd, 3rd)
treats:
- septicaemia
- pneumonia
- meningitis
- biliary tract infections
- UTIs
- sinusitis
Examples:
- cefalexin
- cefuroxime
- cefotaxime
- cefadroxil
- complication: overuse facilitates emergence of C. difficile
Describe how vancomycin works and the problem with resistance
- binds to peptide chain of peptidoglycan
- interferes with elongation of peptidoglycan backbone
- very specific interaction with D-Ala-D-Ala (so minimal resistance)
- resistance in MRSA and some strep/entero-cocci
Describe how bacitracin works and what it can be used for
- bactericidal
- interferes with dephosphorylation of lipid carrier which moves early cell wall components through membrane
- can be used in ointment to treat skin and eye infections by streptococci/staphylococci
What antibiotics are folate antagonists?
- sulphonamides
- trimethoprim
Describe how sulphonamides and trimethoprims work
- act through inhibition of folate pathway in bacteria (important in cell metabolism)
- bacteria must make own supply of folate (but we do not)
- makes bacteria susceptible to drugs which interfere with folate metabolism (selective toxicity target)
What are the clinical uses of sulphonamides and trimethoprim?
- trimethoprim: community UTIs
- sulphamethoxazole used with pyrimethamine for drug-resistant malaria and toxoplasmosis
- can both be used in combination as Co-trimoxazole for
- toxoplasmosis
- with other drugs for opportunistic infections in AIDS (eg. pneumocystis jiroveci)
Describe how chloramphenicol, streptomycin, erythromycin and tetracycline interfere with the bacterial ribosome
- chloramphenicol: binds to 50S r-RNA and inhibits formation of peptide bond
- streptomycin: changes shape of 30S r-RNA and causes m-RNA to be read incorrectly
- erythromycin: binds to 50S r-RNA and prevents movement along m-RNA
- tetracycline: interferes with t-RNA anticodon reading of m-RNA codon
What are examples of macrolides and what are they used for?
- erythromycin
- clarithromycin
- used as alternative to penicillins in patients who are penicillin sensitive
used for:
- mycoplasma chlamydia
- management of LRTI
- leigonella
can be used for:
- corynebacterium (diptheria)
- camphylobacter (diarrhoea)
- chlamydia trachomatis
- toxoplasma gondii
What are the side effects of erythromycin and clarithromycin?
- erythromycin:
- mild gut disturbances
- hypersensitivity reactions
- transient hearing disturbances
- rare - cholestatic jaundice
- clarithromycin: same but with QT prolongation
What are the side effects of clindamycin?
- mainly GI disturbances (but potentially fatal)
- pseudomembraneous colitis (acute inflammation of colon due to necrotising toxin produced by clindamycin-resistant C. diff)
What class is clindamycin in and what is it used for?
- lincosamide class
- active against gram-positive cocci
- active against aerobic species
- combination use against anaerobic sepsis and necrotising faciitis, for staph infections of joints and bones
- used in eye drops for staph conjuntivitis
What are aminoglycosides used to treat and why are they only for serious infections?
- enterobacteriaceae and pseudomonas that give rise to septicaemia and serious UTIs
- hospital acquired pneumonia, respiratory and intra-abdominal infection due to pseudomonas
- rare problematic infections such as brucellosis
- only used in serious infections due to relative toxicity and parenteral administration
What are the side effects of aminoglycosides?
- renal toxicity
- ototoxicity with progressive damage to and destruction of sensory cells in cochlea and vestibular organ of the ear
- results in vertigo, ataxia, loss of balance and auditory disturbances (can cause deafness)
- neuromuscular block (if given with neuromuscular blocker)
What are the cautions for aminoglycosides?
- caution for elderly
- caution with renal failure
- interaction with other renal toxic drugs
- caution in severe sepsis that is causing acute renal failure
What are tetracyclines used to toreat?
- rickettsia
- mycoplasma
- chlamidya
- brucellosis
- cholera
- plague
- lyme disease
- tigecycline used in management of resistant gram negative infection
- COPD
- chronic acne
What are the side effects of tetra cyclines?
- gut upset
- hepatic and renal dysfunction
- photosensitivity
- binding to bone and teeth causing staining, dental hypoplasia and bone deformities
- vestibular toxicity (dizziness/nausea)
What is chloramphenicol used for and why can it only be used as a last resort?
- broad spectrum
- meningitis
- brain abscess
- only used as last resort due to low risk of aplastic anaemia
Describe the action of topoisomerase IV
- tetrameric enzyme of 2 ParC and 2 ParE sub-units
- involved in chromosomal partitioning
- catalyses ATP dependent relaxation of negatively and positively supercoiled DNA and unknotting of un-nicked duplex DNA
- no action against super-coiling
Describe the action of DNA gyrase
- tetrameric enzyme of 2 GyrA and 2 GyrB
- forms transient covalent bond with DNA
- breaks DNA
- passes DNA through break
- repairs break
What are fluroquinolones used for?
- against enterobacteriaceae
- H. influenzae
- B-lactamase-producing N. gonorrhea
- camphylobacter (diarrhoea)
- pseudomonas aeruginosa
- salmonella
What are the quinolone antibiotics?
- naladixic acid
- norfloxacin
- ciprofloxacin
- moxifloxacin
- gatifloxacin
- gemifloxacin
What is the spectrum and use of naladixic acid?
- spectrum: gram negative bacilli
- use: UTI
What is the spectrum and use of nor/ciprofloxacin
- spectrum: gram negative bacilli, mycobacteria, chlamydia
- use: systemic infection
What is the spectrum and use of moxi/gati/gemifloxacin?
- gram positive bacteria
- gram negative bacilli
- mycobacteria
- chlamydia
use: UTI, systemic infection and LRTIs
What is metronidazole and how does it work?
- antiprotozoal agent
- under anaerobic conditions it generates toxic radicals that damage bacterial DNA
What is metronidazole used for?
- anaerobic bacteria like bacteriodes, clostridia, streptococci
- anaerobic infections such as sepsis secondary to bowel disease
- pseudomembranous colitis
- used with other drugs for helicobacter pylori infections that give rise to peptic ulceration
What are the inhibitors of bacterial ribosomal actions?
- macrolides eg. erythromycin and clarithromycin
- clindamycin
- aminoglycosides
- tetracyclines
- chloramphenicol
What are the antibiotics which affect topoisomerase II?
- fluoroquinolones
- quinolone (naladixic acid/norfloxacin/ciprofloxacin)
- metronidazole
