antibiotic classification and mechanisms of action...antibiotic classification and mechanisms of...
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Antibiotic classification andmechanisms of action
Dr Christine Karanja-ChegeMBCHB,Mmed Paeds
KPA 2016
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Outline•Definition•Antibiotic development challenges•Key terminologies•Antibiotic classes•Mechanisms of action of key antibiotics•Highlights on new antibiotics
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Definitiona substance produced by one microorganism that selectively kills or inhibits
the growth of another.
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Challenges of antibiotic development
• the global antibiotic resistance pandemic heralds a postantibiotic era as bad as the pre antibiotic era.
• there is also a decline in the development of new antibioticclasses as pharmaceutical companies direct their effort andfunding to chronic illnesses with a potential for long termrevenue
• between 1998 and 2003 only 9 new antibiotics compared to 16new ones betweeen 1983 and 1987.
• following 911, drug companies are directing their efforts todrugs and vaccines for fighting bioterrorism,
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History of antibiotic development
1928 :Alexander Fleming notedmould of the genus penicilliumcontaminating one of his culturespreventing the growth of bacteria.
1935: Domagk , sulphonamide –synthetic dye
1941: clinical trials of penicillin-Florey and Chain
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Bacteriostatic vs bactericidal activity
• Bactericidal- kill susceptible bacteria; bacteriostatic-inhibit growth ofbacteria, hosts immune responses necessary to eradicate baceria
• Not absolute terms: action depends on in vitro growth conditons, bacterialdensity, test duration
• Bactericidal action necessary in endocarditis, meningitis, osteomyelitis,neutropenia – host immune system not adequate in these sites andconsequences of incomplete killing grave
• Disadvantage of bactericidal: rapid bacterial lysis in meningitis withoverwhelming inflammatory response with increased mortality
• Advantage of bacteriostatic: clindamycin in staph TSS effective in inhibitingTSST-1 production without excessive inflammatory response
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Mechanisms of action
• antibiotics act by disrupting various molecular targetswithin bacteria and cell surface, preventing growth orinitiating killing.
• 3 broad mechanisms:• Disrupt bacterial cell envelope• Block production of new proteins• Inhibit DNA replication
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GROUP EXAMPLES MOA PROPERTIES
Beta-lactams PenicillinsCephalosporinsCarbapenemsmonobactams
Inhibit cell wallsynthesis
BactericidalTime dependentLong PAE on g+ve(carbapenemsalso g -ve)
Glycopeptides VancomycinTeichoplaninTelavancin
Inhibit cell wallsynthesis
Time dependentPAE
Macrolides andketolides
AzithromycinTelithromycinErythromycinclarithromycin
Inhibit proteinsynthesis
BacteriostaticTime andconcentrationdependentLong PAE
Aminoglycosides GentamicinAmikacinTobramycinNetilmicinstreptomycin
Inhibit proteinsynthesis
BactericidalConcentrationdependentPAE
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GROUP EXAMPLES MoA PROPERTIES
Tetracyclines andGlycylcyclines
TetracyclineTigecyclineDoxycyclineMinocycline
Inhibit proteinsynthesis
BacteriostaticTime dependentLong PAE
Quinolones CiprofloxacinNorfloxacinLevofloxacinmoxifloxacin
Inhibit DNA gyrase BactericidalConc. dependentLong PAE
Quinolones CiprofloxacinNorfloxacinLevofloxacinmoxifloxacin
Inhibit DNA gyrase BactericidalConc. dependentLong PAE
lincosamides clindamycin Inhibits proteinsynthesis
Bactericidal/ staticTime depedentPAE
Streptogramins Quinupristin/dalfopristin
Inhibits proteinsynthesis
BactericidalPAEConc.dependent
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GROUP EXAMPLES MOA PROPERTIES
oxalidinones linezolid Inhibits proteinsynthesis
BacteriostaticTime dependentPAE
lipopeptides daptomycin Destroys cellmembranestructure
BactericidalConc.dependentLong PAE
polymixins ColistinPolymixin B
Destroys cellmembranestructure
BactericidalConc.dependentPAE
ansamycins rifampicin Inhibits proteinsynthesis
BactericidalLong PAE
chloramphenicol Inhibits proteinsynthesis
Bacteriostatic
Sulfa drugs Sulfamethoxazole-trimehoprimdapsone
Inhibits DNAsynthesis
BactericidalConc.dependent
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Structure of the bacterial cell wall
• Rigid peptidoglycan layer –alternating amino sugars(NAG andNAM) crosslinked by peptidechains
• Transpeptidation is the final stagein cross linking of the linear glycanchains.
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Cell wall synthesis inhibitors: β lactam antibiotics
• the β lactam ring mimics the D-alanyl-D alanine portion of the peptide chainthat is normally bound by pbps thatassemble the peptidoglycan layer
• This prevents cross linking of theglycan strands leading to bacterial lysis
β lactam ring
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Beta lactams
penicillins cephalosporins carbapenems monobactams
1st gen 2nd gen 3rd gen 4th gen 5th gen
Natural penicillinsPenicillin GPenicillin VBenzathine PProcaine PPenicillinase RMethicillinNafcillinCloxacillinaminopenicillinsAmoxycillinampicillinExtended spectrumTicarcilinPiperacilincarbenicillin
ImipenemMeropenemErtapenem
aztreonam
CefadroxilCephalexinCephradinecefazolin
CefaclorCefamandoleCefuroximecefoxitin
CefotaximeCeftazidimeceftriaxone
cefepime Ceftarolineceftobiprole
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Spectrum of activity: PenicillinsNatural penicillins
G+ve bacteria: streptococci,L.monocytogenes some anaerobes,some spirochaetes, G-ve:N.meningitidis,some H. Infl
Penicilinase RS. aureus, S. Epidermidis
AminopenicillinsSimilar to natural penicillins withadditional G-ve:E.coli, P. Mirabilis,S.enterica, Shigella spp.
Aminopenicillin/ B lactamaseInhibitors
Sulbactam and clavulanateinactivate the B lactamases andbroaden aminopenicillin activity:Some S. Aureus, manyenterobacteriaceae, clostridia exceptdifficile, Bacteroides spp
Extended spectrump. aeruginosa
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Spectrum of activity: Cephalosporins• Each successive generation has
broader activity against aerobic G-ves.
• Limited activity against anaerobes• Lack activity against L.
Monocytogenes and enterococci• 1st gen: good cover for aerobic
G+ve cocci(staph/strep), some G-ves.
• 2nd gen: increased activity againstaerobicG-ve andfacultative(E.coli,P.mirabilis,H.infl,B.fragilis
• 3rd gen: in addition, activity againstB burgdorferi, greater activityagainst aerobic G-ve than 2nd gen,shortlived activity againstenterobacteriaceae, no activityagainst p.aeroginosa exceptceftazidime
• 4th and 5th gen: goodantipseudomonal and antistaphcover, also enterobacteriaceae
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Carbapenems• Very broad spectrum (G+ve and –ves, anaerobes)due to:• Small molecules with charge characteristics that allow
them to use porins in the OM of G-ve bacteria to accessthe PBPs
• Resistant to B lactamases• Affinity to broad range of PBPs
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Monobactams• Aztreonam• Single Beta lactam ring• Very good G-ve cover(Neisseria, Haemophilus spp. Intermediate on
P.aeruginosa), poor activity on G+ves, anaerobes• No cross reaction in Beta lactam allergy
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Cell wall synthesis inhibitors: Vancomycin• like beta lactams,binds to the D-
alanyl-D-alanine portion of thepeptidoglycan layer preventing thepbps from adding them to thepepidoglycan layer
• Effective against nearly all aerobicand anaerobic G+ves including C.difficile, no activity on G-ves
• Emerging R against enterococci
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Antibiotics that inhibit protein synthesisAntibiotics that inhibit protein synthesis
tetracycline aminoglycosides macrolides others
Tetracycline
Oxytetracycline
Demeclocycline
Minocycline
doxycycline
Streptomycin
Neomycin
Gentamicin
Amikacin
tobramycin
Erythromycin
Clarithromycin
Azithromycin
Roxithromycin
spiramycin
Chloramphenicol
Oxalidinones
Ketolides
Lincosamides
streptogramins
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Protein synthesis in ribosomes
• Ribosomes in bacteria – 70s(50s&30s);eukaryotes 80s
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mechanisms of protein synthesis inhibitors
• Interact with variouscomponents of the bacterialribosome and inhibit its function
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Aminoglycosides★positive charge allows them to bind
to the negatively charged outermembrane with formation oftransient holes through whichantibiotic molecules move.★ penetrate the inner cytoplasmic
membrane and bind the 30Ssubunit of the bacterial ribosomeinhibiting synthesis of new proteinsfrom mRNA★ Good activity against aerobic G-
ves, no activity on anaerobes
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Macrolides• bind tightly to the 50s
subunit preventing exit ofthe newly synthesizedpeptide and hence blockingprotein production.
• Active against a broad varietyof bacteria: some G+ves, G-ves, atypicals, somemycobacteria andspirochaetes
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Tetracyclines and Glycylcyclines• interact with the 30s subunit
of the bacterial ribosomeand prevent binding by tRNAmolecules blocking proteinsynthesis
• Active against some aerobicG+ves, some aerobic G-ves,atypicals and spirochaetes
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Chloramphenicol• binds the 50s subunit of the
ribosome blocking the binding oftRNA loaded with an amino acid
• Less limited use in resource richdue to toxicity concerns-reversibledose dependent BM suppression
• Broad spectrum: aerobic G+ves,aerobic G-ves, anaerobes andatypicals
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Clindamycin• Lincosamide antibiotic• bind to the 50s subunit of the
bacterial ribosome and inhibitprotein synthesis
• Active against aerobic G+ves andanaerobes
• No activity on aerobic G-ves• Associated with C. Difficile colitis
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Streptogramins• quinipristin/dalfopristin are
two macrocyclic compoundseach of which binds to the50s subunit of thebacterialribosome to inhibit protensynthesis
• Work synergistically againstG+ves including MRSA,penicillin R strep pneumo,some VRE
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Linezolid• oxazolidinones• bind to the 50s subunit of the
ribosome preventing associationwith the 30s subunit
• also inhibits protein syntheis bypreventing formation of the firstpeptide bond
• Activity against aerobic G+vesincluding MRSA,VRE but notapproved for penicillin R sterppneumo
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Antimetabolites:Sulfa drugs
• trimethoprim-sulfamethoxazoleand dapsone
• Inhibitors of folic acidsynthesis(bacteria cannot usepreformed folic acid)
• tmp inhibits bacterial growth bypreventing the synthesis oftetrahydrofolate
• Sulfonamides and sulphones- PABAanalogues, competitive inhibitionof dihydropteric acid
• Broad variety of aerobic G+ve andG-ve susceptible. No activity onatypicals and anaerobes
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Inhibitos of DNA synthesis:Quinolones
• All except nalidixic acid havefluorine added to enhance potency
• Bind to the A sub-unit of DNAgyrase, prevent supercoiling ofDNA
• Broad variety: G+ve, G-ve, atypicalsand mycobacteria
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Inhibitors of RNA synthesis:Rifamycins
• Inhibit bacterial RNApolymerase
• Activity against staph, N.Meningitidis and H. Influenza
• Used in combinationtreatment for mycobacterialinfections
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Metronidazole• Small molecule that can passively
diffuse into bacteria.• Has a nitro group that must be
reduced(accept electrons) for it to beactive.
• Anaerobic bacteria can donateelectrons to this nitro group enabling itto form free radicals that lead tobreaks in DNA molecules andsubsequent cell death
• Active against G+ve and –ve anaerobesincluding C. Difficile andmicroaerophilic H. pylori
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Tigecycline• Structurally related to minocycline• Binds 30s preventing entry of tRNA similar to TTCs• Has an additional N,N,-dimethylglycylamido group that increases affinity
for the ribosomal target – broader spectrum , less R
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Lipopeptides• Daptomycin• lipid portion inserts into the bacterial cytoplasmc menbrane forming an
ion conducting channel that allows ions to escape from the bacteriumleading to cell death
• Active against aerobic G+ves, also MRSA, penicillin R S.pneumo, someVRE
• No activity against G-ves,poor activity in lungs
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Lipoglycopeptide: telavancin• New antibiotic for vancomycin R organisms• Dual mechanism of action: cell wall synthesis inhibiton –binds to the
terminalacyl-d-alanyl-d-alanine chains preventing cross-linking; disruptscell membrane as well
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Video links
https://www.youtube.com/watch?v=qBdYnRhdWcQ beta lactams
https://www.youtube.com/watch?v=oC21vLFtsjo&index=21&list=PLljUvnIqpbeM4w36nCziqnNZGwLzrPrul macrolides
https://www.youtube.com/watch?v=IkKZ_gxAOXI quinolones
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Thank you for your time!