Antibiotic classification andmechanisms of action

Dr Christine Karanja-ChegeMBCHB,Mmed Paeds

KPA 2016

Outline•Definition•Antibiotic development challenges•Key terminologies•Antibiotic classes•Mechanisms of action of key antibiotics•Highlights on new antibiotics

Definitiona substance produced by one microorganism that selectively kills or inhibits

the growth of another.

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,

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

Protein synthesis in ribosomes

• Ribosomes in bacteria – 70s(50s&30s);eukaryotes 80s

mechanisms of protein synthesis inhibitors

• Interact with variouscomponents of the bacterialribosome and inhibit its function

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

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

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

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

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

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

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

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

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

Inhibitors of RNA synthesis:Rifamycins

• Inhibit bacterial RNApolymerase

• Activity against staph, N.Meningitidis and H. Influenza

• Used in combinationtreatment for mycobacterialinfections

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

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

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

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

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

Thank you for your time!