Antibiotic Resistance in Bacteria Flashcards
What are Antibiotics?
= substance produced or derived from certain fungi, bacteria or other organism
= can destroy or inhibit the growth of other microorganisms
= antibiotics widely used in prevention and treatment of infectious diseases
= extremely diverse group of products called secondary metabolites:
= complex organic molecules that are non-essential cell growth or reproduction
What are some antibiotic mechanisms?
Inhibit cell wall synthesis
= B-lactams / SCCMec
= e.g. penciliins
Inhibit protein synthesis
= aminoglycosides
= e.g. streptomycin
Disrupt unique components of the cytoplasmic membrane
= polyenes
= (amphotericin B - fungi only)
Inhibit general metabolic pathway not used by humans
= sulfonamides (e.g. sulfanilamide)
Inhibit nucleic acid synthesis
= (fluoro)quinilones - DNA gyrase
= rifampicin-prokaryotic RNA polymerase
Block pathogen recognitions of or attachment to its host
= attachment antagonists (mainly viral)
= antibiotic more toxic to the pathogens and must be less toxic to the host
How does resistance to beta-lactam antibiotics occur?
Beta lactamases
= degrafe beta lactam ring and inactivates antibiotic
= bypasses antibiotic by providing alternative PBPs
e.g. Penicillin resistance
What is the mode of action for Antibiotics affecting protein synthesis?
Streptomycin
= changes ribosome shape
= can’t read mRNA
Tetracycline
= block docking site of tRNA
Clarithromycin
= blocks proper mRNA movement through ribosome
= synthesis stops
What is the mode of action for Antibiotics affecting metabolic pathways?
e.g. PABA (structural analog - sulfonamide)
= binds to enzyme
= released dihydrofolic acid
Sulfonamide will inhibit folic acid synthesis
= blocks pathway
= no dihydrofolic acid produced
= no DNA synthesis
= no bacterial growth
How does development of resistance in bacteria occur?
Population of microbial cells
Exposure to drug
Sensitive cells inhibited by exposure to drug
Remaining population grows over time
Most cells now resistance
What are the causes of Antimicrobial Drug Resistance?
= incorrect prescribing practices
= non-adherence by patients
= counterfit drugs
= use of anti-infective drugs in animals and plants
= loss of effectiveness
= community-acquired
= hospital-acquired
What are the consequences of Antimicrobial Drug Resistance?
= prolonged hospital admissions
= higher death rates from infection
= requires more expensive, more toxic drugs
= higher health care costs
What are antibiotic resistance reservoirs?
Resistome
= collection of all the antibiotic genes and their precursors in both pathogenic and non-pathogenic bacteria
What are the 5 different types of genes that make up antibiotic resistance genes?
Resistance genes found in pathogenic bacteria
Resistance genes in environmental bacteria
Resistance genes found on antibiotic produces
= e.g. soil-dwelling bacteria and fungi that encode resistances
Cryptic resistance genes
= embedded in bacterial chromosome but do not obviously confer resistance
= cus their level of expression is low or not expressed
Precursor genes
= do not confer antibiotic resistance
= encode protein that confer some basal level activity against antibiotic molecule / have affinity to molecule
= interaction may evolve to a full resistance gene with correct selection pressures
(groups not independent - some overlapping)
What are some global reservoirs for antibiotic reservoirs?
Soil
Freshwater (+aquaculture)
Oceans
Global Resistome
What are the different types of resistance?
Passive
= antibiotic has no target or cannot enter cell
= has no action
Mutation
= target site changes so antibiotic is ineffective
Acquired
= actively acquired resistance
= genetic elements - e.g. plasmids
What is an example of mutation (in Antibiotic Resistance)?
Streptomycin
= binds to 16S rRNA of 30S subunit of bacterial ribosome
= causes inhibition of protein synthesis
= mutation 16S rRNA gene by point mutation, insertion, inversion, deletion or duplication
= changes active site and makes streptomycin ineffective
What is an example of Aquired antibiotic resistance?
Horizontal gene transfer
= acquisition of genes from other microorganisms
= transformation
= transduction
= conjugation
(often plasmid encoded aided by transposons and integrons)
What are modular mobile elements?
= transposable elements
= DNA sequences with ability to move (transpose) themselves to different locations within the genome
2 main types
= DNA transposons = physically cut themselves out of original location and insert into new location in the genome
= Retrotransposons = use copy and paste mechanism, use own reverse transcriptase to create DNA copy of themselves from RNA sequence then insert this copt into new location in genome
What is an example of a multi-resistance plasmid?
= pFBAOT6
= IncU multi-resistance plasmid
= 87,478 bp in length
= 94 predicted coding sequences
(only 12 not assigned a possible function)
= core functions in the first 31 kb
= genetic load region 54 kb
(class I integron, several transposable elements, potential composite transposon of 43 kb)
What is the model for MecA induction?
- Antibiotic exposure
= S. areus exposed to beta-lactam antibiotics - Activation of sensor kinase
= antibiotic triggers activation of sensor kinase
= (membrane bound protein that detects presence of antibiotic and transmits signal to cytoplasm) - Phosphorylation of response regulator
= signal received by response regulator
= becomes phosphorylated and activates the transcription of downstream genes - Activation of mecA expression
= one of the downstream genes activated
= encodes regulatory protein that controls expression of antibiotic resistance genes - Expression of antibiotic resistance genes
= mecA binds to and inhibits the activity of another regulatory protein: Blal
= Blal normally repressed antibiotic resistance genes
= inhibition leads to expression of these genes
(EXTRA READING)
What is the action of penicillin?
Penicillin binds to and inhibits activity of penicillin binding proteins (PBPs)
= bacteria are then unable to build new cell wall material
= their existing cell wall becomes weakened and susceptible to damage
= these bacteria are unable to grow and divide properly
= eventually killed by the antibiotic
Resistance through PBP2A
= PBP2A structurally different, not inhibited by beta-lactam antibiotics
= carry out own cell wall synthesis activity
= bacteria maintain structural integrity and survive
