Bacteria Chapter 7: Antibiotic Therapy Flashcards
What are bactericidal antibiotics?
antibiotics that kill bacteria
What are bacteriostatic antibiotics?
antibiotics that inhibit growth of bacteria without killing
Can antibiotics be derived from bacteria themselves?
yes
ie. penicillin
What are the different modes of action of different antibiotics?
- interfere with bacterial cell wall biosynthesis – inhibits transpeptidation reactions during PG biosynthesis
- destabilize cytoplasmic membrane
- interfere with protein synthesis by binding to ribosome and inhibiting its function
- interfere with DNA unwinding during DNA replication
- interfere with DNA-directed RNA polymerase activity – inhibits transcription
- interfere with folic acid vitamin metabolism
What must antibiotics target?
- bacterial metabolic process not found in host cell (ie. PG synthesis)
- bacterial molecule/structure that is sufficiently different from the analogous molecule/structure in host cell
What are some parts of bacterial metabolism targeted by antibiotics?
- cell wall synthesis
- DNA replication
- RNA elongation
- DNA-directed RNA polymerase
- protein synthesis
- lipid biosynthesis
- cytoplasmic membrane structure and function
- folic acid metabolism
β-lactams (type of antibiotic)
What are some examples of this type of antibiotic?
- penicillin
- ampicillin
β-lactams (type of antibiotic)
How do they kill bacteria?
interfere with cell wall PG synthesis by binding to, and inhibiting enzyme that forms amino acid cross-links between glycan chains
- results in osmotic lysis in hypotonic environment
- normally: new PG needs to be added to pre-existing PG (double) in order for bacteria to divide – inhibiting this inhibits bacterial growth
What are desirable attributes of antibiotics?
(not all antibiotics have all attributes)
- solubility in body fluids, with good penetration to the infection site
- effectiveness against bacteria at low concentration
- low frequency of resistance development
- low rate of breakdown or excretion in body
- low toxicity, well-tolerated, non-allergenic
Does treatment of bacterial infection with antibiotics affect microbiota?
yes – can destroy both microbiota and pathogenic bacteria
ie. when antibiotic is given orally, some members of the microbiota may be affected, and opportunistic pathogens may be able to establish themselves and cause disease
Give 2 examples of how antibiotics can destroy microbiota and pathogenic bacteria.
- overgrowth of Clostridium difficile in intestine – leads to watery diarrhea and colitis (inflammatory disease of colon)
- overgrowth of yeast Candida in vagina
What happens to microbiota when antibiotic treatment is stopped?
eventually reestablishes
What are the 4 reasons why bacteria can vary in their individual sensitivity/resistance to antibiotics?
- antibiotic exclusion
- antibiotic inactivation
- antibiotic efflux
- target site alteration
What is antibiotic exclusion?
effective barriers to antibiotic penetration
ie. Gram-negative bacteria have OM as additional permeability barrier – more resistant than Gram-positive bacteria
What is antibiotic inactivation?
ability to make antibiotic inactivating enzymes
ie. enzyme β-lactamase inactivates penicillin
What is antibiotic efflux?
bacteria membrane proteins transport antibiotics out of cell before any damage is done
What is target site alteration?
target site is altered so antibiotic cannot bind
ie. vancomycin resistant Staphylococcus aureus (VRSA)
- vancomycin interferes with PG cross-linking enzyme by binding to certain cross-linking amino acids
- VRSA have lactate in place of alanine at a critical site which prevents vancomycin from binding
What is the disk diffusion antibiotic susceptibility test?
- Bacterial isolate is spread evenly onto surface of agar plate so that when bacteria grows, it will form a lawn
- Paper disks impregnated with various antibiotics are placed on surface of plate
- Antibiotic is allowed to diffuse into culture medium
- As bacteria on lawn grow, they are inhibited by varying degrees of antibiotic diffusing from the disk
What does a disk diffusion antibiotic susceptibility test indicate?
inhibition of bacterial growth around a disk (zone of inhibition) following incubation indicates sensitivity to the particular antibiotic that was impregnated in the disk
What is the size of the zone of inhibition of a disk diffusion antibiotic susceptibility test dependent on?
- diffusion rate of antibiotic
- degree of sensitivity of bacterium
- growth rate
What does the size of the zone of inhibition of a disk diffusion antibiotic susceptibility test tell us?
standard zones of inhibition have been established for each antibiotic
- if the zone is = or > than standard, organism is sensitive to the antibiotic
- if the zone is < than standard, organism is resistant to the antibiotic
How can a normally sensitive bacterium acquire resistance to an antibiotic?
antibiotic resistance is a genetically encoded trait – therefore, change its genes
- changes may occur to existing genes through normal random spontaneous mutation that occurs as part of DNA replication during cell division
- mutations are then passed to progeny of newly resistant cell (vertical gene transfer)
- sensitive bacteria may acquire resistance to antibiotic by acquiring new gene(s) derived from a resistant organism by horizontal gene transfer
What are the 3 processes by which horizontal gene transfer can occur?
- transformation
- transduction
- conjugation
What is vertical gene transfer?
genes are passes to the progeny of the newly resistant cell
What is horizontal gene transfer?
gene is acquired by deriving it from a resistant organism
What is transformation?
DNA from a dead antibiotic resistant donor bacterium is taken-up by an antibiotic sensitive recipient bacterium
What is transduction?
virus infects and kills an antibiotic resistant donor bacterium
when virus infects an antibiotic sensitive recipient bacterium, some antibiotic resistance genes from the donor are transferred to the recipient
What is conjugation?
autonomously replicating double-stranded DNA element (plasmid) carrying antibiotic resistance genes is transferred from antibiotic resistant donor to sensitive recipient by cell-to-cell contact
Why is the prevalence of antibiotic resistance in bacterial populations increasing?
widespread killing of sensitive bacteria by overuse of antibiotics by humans in medicine and agriculture means that now it is more likely an infection will be caused by a pathogenic bacterium that is also resistant to antibiotics
What is the increasing prevalence of resistance to methicillin in Staphylococcus aureus associated with?
increased prevalence of plasmid-carrying gene for alternate PG cross-linking enzyme that is not a suitable target for methicillin
What are some methods to deal with the antibiotic resistance problem?
- find new natural antibiotics and/or synthesize new antibiotics
- exploit cationic antimicrobial peptides (components of immune system)
- exploit phage therapy
- target quorum sensing
- target biofilm formation (interfere with EPS synthesis, quorum sensing, inhibit adherence)
Why can we use an antibiotic that affects RNA synthesis in the pathogen?
human RNA polymerase has different structure than bacteria – antibiotics don’t bind to our RNA polymerase
Why can we use an antibiotic that affects protein synthesis in the pathogen?
human ribosomes have different structure – antibiotics don’t interact with our ribosomes
Why can we use an antibiotic that affects cell wall biosynthesis in the pathogen?
humans don’t have cell wall
Why can we use an antibiotic that affects folic acid metabolism in the pathogen?
humans don’t make folic acid – obtained from our diet instead
Why can we use an antibiotic that affects DNA replication in the pathogen?
human DNA gyrase (unwinds DNA) has different structure that doesn’t interact with antibiotic
Why can we use an antibiotic that destabilizes cytoplasmic membrane in the pathogen?
antibiotic would not be able to act with membrane of eukaryotic cells
Prior to being released into the general population for use as a therapeutic agent, antibiotics are carefully screened in a series of clinical trials. In addition to selective toxicity, what other attributes must be carefully considered when designing a new antibiotic?
- soluble in body fluids
- able to reach infection site quickly and in sufficiently high concentration – able to remain in body for reasonable amount of time
- no or minimal side effects
- can’t trigger allergic response
- bacteria should not be able to easily develop resistance to it
- able to act against most pathogenic bacteria
