dr. Agus Eka Darwinata, Ph.D Genetika Mikroorganisme AED
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dr. Agus Eka Darwinata, Ph.DGenetika Mikroorganisme
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The Central Dogma
Mechanism of Antimicrobioal Resistance
Gene and Genome
Polimerase Chain Reaction
Mutation
TOPIC
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Gene and Genome
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Genom adalah keseluruhan informasi genetik (gen) yang dimiliki suatu sel atau organisme.
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Human Genome
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Bacterial Genome
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9181 bp
Viral Genome
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Genome-Gene Analogy
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The Central Dogma
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The Central Dogma of Biology
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DNA Structure
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Replication
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Transcription
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Translation
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Translasi protein (cont.)
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Mutation
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Mutation
• Changes in base sequece of DNA and inheritable
• Can be:• Harmful• Lethal• Helpful• Silent
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Mutation
Point Mutation Frame Shift Mutation
missense
silent
nonsense
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Genetic Transfer
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Genetic Information Flow in Bacteria
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Genetic Transfer
• Genetic transfer results in genetic variation
• Genetic variation needed for evolution
• Three ways:• Transformation• Conjugation• Transduction
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Transformation• Genes transferred from one bacterium to another by virus.
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Conjugation• Plasmid transferred from one bacterium to another via a pilus.
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Conjugation cont…
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PCR
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Polymerase Chain Reaction•PCR allows us to produce rapidly (amplify) a billion copies of DNA without needing a living cell.
•These large quantities are then easily analyzed.
•PCR recipe:
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Polymerase Chain ReactionAmplification of nuc gene of S. aureus
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Result
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Mechanism of Antimicrobioal
Resistance
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Alteration of bacterial membranes
Bypass of antibiotic inhibition
Enzymatic inhibition
Alteration of bacterial protein targets
Promotion of anntibiotic efflux
Mechanism of Antimicrobioal Resistance
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Enzymatic inhibition“bacteria produce enzymes to inhibit the activity of antibiotic”
•Betalactamase by splitting beta-lactam ring.
• 340 different type of beta-lactamases.
•Extended spectrum beta-lactamases (ESBLs) is the most problematic.
•ESBL producing organism (e.g., Klebsiella, Proteus, Pseudomonas, Citrobacter, and E. coli) extremely resistant. Therapy limited to carbapenem.
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Enzymatic inhibition“bacteria produce enzymes to inhibit the activity of antibiotic”
•1990’s carbapenemases producer was found in Klebsiella pneumoniae (KPC), can be transmit via a plasmid to multiple other genera.
• In late 2010, New Delhi metallo-beta-lactamase1 (NDM-1), in E. coli and Klebsiella pneumoniae, resistant to all antibiotic except tigecycline and colistin.
•Carbapenemase-resistant enterobacteriaceae (CRE) is a huge health concern worldwide.
•Greatest risk factor: long stay in ICU with carbapenem therapy.
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Alterations of bacterial membranes“to prevent entry of antibiotics into bacteria”
•Outer Membrane Permeability. Mutation result in alteration in porin. Pseudomonas aeruginosa resistance to imipenem.
• Inner Membrane Permeability. Altered the active electron t r a n s p o r t ( r a re ) . S t a p h y l o c o c c u s re s i s t a n t t o aminoglycoside. Induced by long-term aminoglycoside therapy.
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Promotion of Antibiotic Efflux“actively pump the antibiotics out of the bacteria”
•Pseudomonas aeruginosa and Staphylococcus aureus resistace to tetracycline.
• Induced by subtherapeutic concentration of tetracycline.
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Alterations of bacterial protein targets“which make these target unrecognizable to antibiotic”
•Alteration of Ribosomal Target Site. Resistance to a wide variety of antiribosomal agent, including tetracyclines, macrolides, clindamycin, and aminoglycosides. Alteration of ribosomal binding sites. Staphylococcus aureus and Enterococci species resistance to macrolides.
•Alteration of Cell Wall Precursor Targets. vanA induces the synthesis of newly modified peptidoglycan. E.coli and S. aureus resistance to vamcomycin and teicoplanin (glycopeptide antibiotics).
•Alteration of Critical Enzymes. Alteration in penicillin binding proteins (PBPs)/transpeptidase. Gram positive resistance to beta-lactam antibiotics.
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Bypass of Antibiotic Inhibition“allowing bacteria to find alternate pathways to survive when
one pathway is blocked by an antibiotic”
•Enterococci (thymidine dependent organism) utilize exogenous supplies of thymidine for enzyme activity and are thus highly resistant to trimethoprim which blocks endogenous production of thymidine by bacterial enzymes.
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Thank you
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