antibiotics and resistance Flashcards
Antibiotics
a class of chemotherapeuticagents • Chemotherapeutic agents are chemical compounds used to treat disease
• Antimicrobials
• Antimicrobials destroy pathogenic microbes or
inhibit their growth within host
• Antibiotics
• Antibiotics destroy or inhibit bacteria
• Most antibiotics are microbial products or their
derivatives
where do many antibiotics come from
many are derived from microbes as compounds produced to compete with other microbes
• selective toxicity
– ability of drug to kill or inhibit pathogen while
damaging host as little as possible
• therapeutic dose
– drug level required for clinical treatment
• toxic dose
– drug level at which drug becomes too toxic for patient
i.e., produces side effects
• therapeutic index
– ratio of toxic dose to therapeutic dose
• Bacteriocidal antibiotics
• Bacteriocidal antibiotics
– kill bacteria
• Bacteriostatic antibiotics
– inhibit growth of bacteria
Broad-spectrum antibiotics
– attack many different bacteria (Gram + and Gram -)
Narrow-spectrum antibiotics
– attack only a few different bacteria
Determining the Level of Antimicrobial Activity
effectiveness expressed in two ways: MIC and MBC
MIC
– minimal inhibitory concentration (MIC)
• lowest concentration of drug that inhibits growth of pathogen
MBC
minimal bacteriocidal concentration (MBC)
• lowest concentration of drug that kills pathogen
tests used to detemrine MIC/MBC
dilution susceptibility and disk diffusion
dilution susceptability
• involves inoculating media containing different concentrations of drug
– broth or agar with lowest concentration showing no growth is MIC
– if broth used, tubes showing no growth can be subcultured into drug-free medium
• broth from which microbe cannot be recovered is MBC
Disk Diffusion Tests
- disks impregnated with specific drugs are placed on agar plates inoculated with test microbe
- drug diffuses from disk into agar, establishing concentration gradient
- observe clear zones (no growth) around disks
table for disk diffusion tests
radius of inhibiton zone: larger= able to inhibit at lower concentrations= lower MIC
may be resistant with smaller inhibition zone
Kirby-Bauer method
- standardized method for carrying out disk diffusion test
- sensitivity and resistance determined using tables that relate zone diameter to degree of microbial resistance
- table values plotted and used to determine if concentration of drug reached in body will be effective
Measurement of Drug
Concentrations in the Blood
when effective?
tests?
concentration of drug at infection site must be > MIC to be effective
• microbiological, chemical, immunological, enzymatic, or chromatographic assays can be used to determine concentration of drug in blood
Factors Influencing the Effectiveness of Antimicrobial Drugs
- ability to reach site of infection
- ability to exceed MIC of pathogen
- susceptibility of pathogen
Ability of drug to reach site of infection factors
• depends in part on mode of administration
– oral: some drugs destroyed by stomach acid
– topical
– parenteral routes: nonoral routes of administration
• drug can be excluded by blood clots or necrotic tissue
Factors influencing ability of drug to reach concentrations exceeding MIC
- amount administered
- route of administration
- speed of uptake
- rate of clearance (elimination) from body
Susceptibility of pathogen to drug factors
- Does a drug require bacterial cell growth to be effective? (can spores be targeted)
- Speed of action of a drug
concepts for Mechanism of Action of Antimicrobial Agents, how we target/ideally?
- can impact pathogen by targeting some function necessary for its reproduction or survival
- Ideally, targeted function is very specific to pathogen= high therapeutic index– Not always possible
Mechanisms of Action of Antimicrobial Agents
target bacterial cell wall
inhibition of protein synthesis
inhibition of NA synthesis
antimetabolites
Disruption of bacterial cell wall drug classes
b-lactams
Glycopeptides
Polypeptides
Others
how can we target the cell wall?
peptidoglycan unique to both +/- bacteria, most pathgens contain this
Peptidoglycan Synthesis basic steps and diagrammed
– peptidoglycan repeat unit forms incytoplasm
• involves use of uridine diphosphate (UDP) as a carrier
– repeat unit then transported across membrane by bactoprenol (“lipid”)
– repeat unit attached to growing peptidoglycan chain
– cross-links formed by transpeptidation
transpeptidation
how cross links form in peptidoglycan
exchange of one peptide bond for another
b-lactam function
b-lactam antibiotics inhibit transpeptidation
types of B lactams (names)
penicillins
cephalosporins
carbapenems
monobactams
different penicillins
many with different side chains modifications for variable properties
b-lactamase inhibitors
Not antibiotics, but help b-lactam antibiotics by preventing their degradation by b-lactamases
b-lactamases are enzymes produced by some bacteria that are resistant to b-lactam antibiotics
Examples of b-lactamase inhibitors, 1st combo?
Examples of b-lactamase inhibitors: clavulanic acid, sulbactam, and tazobactam
Augmentin was 1st combination = amoxicillin + clavulanic acid
Vancomycin action, counter to this?
Vancomycin binds terminal D-Ala-D-Ala and sterically inhibits addition of peptidoglycan subunits to the cell wall.
Vancomycin binding to existing peptidoglycan chains inhibits the transpeptidation reaction that crosslinks the chains.
mutated d-ala-d-lac can counter this and prevent binding
vancomycin has been important for treatment of?
vancomycin has been important for treatment of antibiotic resistant staphylococcal and enterococcal infections
Vancomycin and teichoplanin are?
Vancomycin and teichoplanin are glycopeptides
Polypeptide names
bacitracins and polymixins
bacitracins action
Prevent recycling of lipid carrier, bactoprenol
polymixins action, usual mode of delivery and why?
Binds phospholipids and disrupts outer and inner membranes of gram negative bacteria (topical because of more general mode of action = toxicity possible)
Cycloserine an along of? How it functions?
second line treatment for?
possible side effect?
Cycloserine is a cyclic analog of alanine, blocks formation of the d-ala/d-ala
Second line treatment for Mycobacterium tuberculosis
- Also crosses blood brain barrier and is an NMDA receptor agonist (with
uses and side effects)
Isoniazid, Ethionamide actions
affecting synthesis of mycolic acid (abundant wax in the cell wall)
glycopeptide antibiotics names
vancomycin & teichoplanin
other antibiotics
cycloserine
isoniazid & ethionamide
ethambutol
Ethambutol action
affecting attachment of mycolic acid in the cell wall
bacterial protein synthesis summarized
- small RNA subunit attatches to mRNA
- charged met tRNA recruited
- forms 30S initiation complex
- large subunit recruited
- forms 70S initiation complex
- elonagtion, charged tRNA brought into A site>peptidyltransferase
reaction> translocation reaction - termination
how can we target bac pro syn
different ribosomes from our own, although toxicity still possible
Oxazolidinones name
linezolid
Oxazolidinones actions
Binds 23S rRNA and prevents formation of 70S initiation complex
Tetracyclines action
Bind 16S rRNA of 30S subunit and prevent binding of aa-tRNA to
A site
Aminoglycosides names
streptomycin
amikacin
gentamycin
tobramycin
Aminoglycosides action
Bind to 30S subunit and distort A site, causing translation misreading, which inhibits protein synthesis
Chloramphenicol/ Lincosamides actions
Bind to 50S subunit and inhibit peptidyltransferase activity= inhibits the peptidyltransferase reaction
Macrolides names
Erythromycin, azithromycin, clarithromycin
Macrolides function
- Bind 23S rRNA in the 50S subunit and block the translocation reaction
- also prevent formation of the 50S subunit
Quinolones names
ciprofloxacin and other -floxacins
Quinolones function
Interfere with type II topoisomerase (DNA gyrase or topoisomerase IV) and
stabilize DNA double strand breaks, prevents DNA from getting untangled/reattached in replication
Rifampin & Rifabutin action
bind to RNA polymerase and prevent
the initiation of transcription
Metronidazole function
- a prodrug with no inherent antimicrobial activity
* produces DNA-damaging radicals under anaerobic conditions via enzymes functioning in anaerobes and microaerophiles
Antimetabolites names
Sulfonamides, trimethoprim, dapsone, and p-aminosalicylic
acid
antimetabolites function
target folic acid synthesis, we do not have this process only bacteria/pathogens
Drug Resistance
Big problem for clinical treatment of infections
Resistance can often be transmitted to other bacteria
possible ways of resistance
impermeable barrier
target modification
antibiotic modification
efflux pump
impermeable barrier
cell wall become imperm to Ab
target mod
target of the Ab is modded (mutation, plasmid, etc), Ab can no longer target effectively
Ab mod
bacteria produces compound to counter the Ab/destroy it
efflux pump
ab actively pumped out of cell before it can act
penicillins, cephalosporins resistance mech
hydrolysis of b-lactam ring by b-lactamase
methicillin resistance mech
change in penicillin-binding protein
tetracyclines resistance mech
efflux pump
oxazolidinones resistance mech
mutations in 23S rRNA
quinolones resistance mech
mutations in genes encoding DNA gyrase and
topoisomerase IV
The Origin of Drug Resistance
• New mutations of bacterial genes that encode the targets of antibiotics
OR
• Pre-existing resistance genes that are transmitted from one bacterium to another
Genetic elements involved in resistance gene dissemination
Plasmids Transducing bacteriophage Bacterial chromosomal genes Transposons Integrons
plasmids and resistance
some can promote their own transfer by conjugation to other cells via sex pili
Transducing bacteriophage
- can package non-phage DNA (= transfer by transduction) allowing resistance transfer
Bacterial chromosomal genes and resistance
- mutations
- transfer by transformation (uptake of DNA)
Transposons and reisistance
- hop into other genetic elements
Integrons and resistance, found?
Integrons
- segments of DNA containing complete sets of genes
- found on plasmids, transposons, and bacterial chromosomes
R plasmids and transposons
transposon for resistance genes may be found on plasmids= R plasmids
Superinfection
development and spread of drug-resistant pathogens
caused by drug treatment, which destroys drug sensitive strains
Killing of normal flora removes the inhibitory effect of the normal flora (which produce antibacterial substances & compete for essential nutrients).
This allows for uninhibited growth of potentially pathogenic bacteria & fungi
Common organisms in Superinfections include:
Clostridium difficile (spore-forming agent of pseudomembranous colitis)
MDR (multi-drug-resistant) gram-negative rods
MRSA (methicillin-resistant Staphylococcus aureus)
Candida or other fungi
Preventing emergence of drug resistance
future solutions?
- give drug in high concentrations
- give two or more drugs at same time
- use drugs only when necessary
• possible future solutions
– continued development of new drugs
– use of bacteriophages to treat bacterial disease
