EXAM 2 Antibiotic Resistance Flashcards
antibiotics are synthesized by ___ or ___
molds or bacteria
naturally occurring antibiotics can be chemically modified to ___
improve/alter their activities
in 1900 prior to antibiotics and vaccines, pneumonia, TB, diarrhea and enteritis, together with diphtheria caused ___ of all deaths
1/3
___ was discovered by alexander fleming in st. mary’s hospital in london, september 1928. it was rediscovered by howard florey ___ years later.
- penicillin
- 10
penicillin production was optimized in the US with the use of ___
new growth media and new molds
how many additional antibiotics have been developed since penicillin was introduced?
over 140
antibiotics save over ___ lives each year in the USA, adding ___ years to US life expectancy
- 200k
- 5-10
which antibiotics target cell wall synthesis/integrity?
- beta lactams
- glycopeptides
- bacitracin
- fosfomycin
which antibiotics target RNA synthesis?
rifampin
which antibiotic targets amino-acyl tRNA synthetase?
mupirocin
which antibiotics target folic acid (tetrahydrofolate) synthesis?
sulfonamides and trimethoprim
which antibiotics target protein synthesis via the 30S ribosome?
aminoglycosides and tetracyclines
which antibiotics target protein synthesis via the 50S ribosome?
- chloramphenicol
- macrolides
- lincosamides
- streptogramins
- everninomycin
- oxazolinonones
- lincosamides
which antibiotics target DNA replication/repair/segregation?
- quinolones
- fluoroquinolones
- metronidazole
over ___ million illnesses and ___ deaths are estimated to be as a result of antibiotic resistance
- 2 million
- 23,000
if the current trend continues, antibiotic resistant bacteria are expected to cause the premature death of ___ million people per year globally by 2050
___ is the rational, optimal use of antimicrobials
stewardship
all medical providers should behave as antimicrobial stewards
what are the 4 major antimicrobial resistance mechanisms?
- restrict antibiotic access of drug to its target
- modify antibiotic target
- modify the antibiotic itself
- modify expression of bacterial factors needed to activate the antibiotic (prodrugs)
describe restricting antibiotic access as an antimicrobial resistance mechanism
- drug can’t get in or drug gets in but gets pumped back out before affecting target
- ex. alter envelop to inhibit uptake or boost expression of efflux pumps
describe antibiotic resistance by modification of the target
- target is altered structurally or target is overexpressed, so you need much more of the drug
- ex. mutation or gain of modifying enzyme (A2580G mutation in 23S rRNA protects against macrolides like erythromycin)
- overexpression of target (change in promoter, regulator, or gene copy number)
describe antibiotic resistance by inactivation of the antibiotic: beta-lactamase
beta lactamase breaks a bond in the beta lactam ring of penicillin to disable the molecule. bacteria with this enzyme can resist the effects of penicillin and other beta lactam antibiotics
describe antibiotic resistance by modification of the antibiotic: aminoglycoside-inactivating enzymes
- targets aminoglycosides
- modifications disrupt hydrogen-boning network used to bind 16S rRNA
what are two ways resistance is acquired?
mutation and horizontal gene transfer
which 3 ways can resistance genes be transferred?
conjugation, transformation, and transduction
in e. coli, resistance to streptomycin can arise due to spontaneous mutation at a rate of 1 in a billion. why is this important?
though rare, the fast growth rates and high numbers of bacteria mean that rare events like this become meaningful
what are 4 important classes of multidrug resistant bacterial pathogens that are becoming increasingly common?
- extended-spectrum beta lactamase producing enterobacteriaceae
- carbapenem-resistant enterobacteriaceae
- clostridium difficle
- super neisseria gonorrhea
describe extended-spectrum beta lactamase producing enterobacteriaceae
26,000 infections due to ESBL strains
1700 deaths per year
$40k excess costs per infection
describe carbapenem-resistant enterobacteriaceae
>9000 healthcare associated infections are caused by CRE each year
about 600 deaths due to resistant klebsiella and e. coli strains per year
describe clostridium difficile
250000 infections per year requiring hospitilization or affecting already hospitalized patients
14000 deaths per year
at least $1 billion in excess medical costs per year
describe super neisseria gonorrhea
246000 drug-resistant infections per year (30% of total gonococcal infections)
what 4 things contribute to the selection and spread of multi-drug resistant strains?
overuse of antibiotics, overpopulation, poor hygiene, and travel
the number of new antibiotics developed and approved has steadily decreased in the past 3 decades, leaving fewer options to treat resistant bacteria. why?
- development of new antibiotics is daunting: costs, pharmacokinetics, potential side effects
- ideally target pathogens with minimal effects on beneficial microbiota
describe antibiotic tolerance
- bacteria that are normally susceptible to antibiotics may be able to tolerate the drugs under some conditions
- antibiotic tolerance contributes to chronic and recurrent/relapsing infections (recrudescence)
- antibiotic tolerance is important
- within intracellular niches
- spores
- within biofilms
- persister cell formation
bacteria present within ___ are often protected from antibiotic treatments
biofilms
>___% of human infections may involve biofilms
65
biofilm formation enhances the ability of bacteria to tolerate antibiotics in what ways?
- extracellular matrix
- altered protein expression
- decreased metabolism
- persister cell formation
- increased genetic exchange
- increased stress resistance
what are persister cells?
dormant bacteria that are insensitive to many stresses and antibiotic treatments
antibiotics have a hard time killing ___, but may still reduce bacterial numbers enough so that the host can regain control.
persisters
describe bacterial resistance to tetracycline as an antibiotic resistance mechanism. what is the mechanism of resistance?
- tetracycline binds to the 16S rRNA in the 30S subunit
- as a modifcation of the target, ribosomal mutation is achieved via mutation or horizontal gene transfer acquisition of a GTPase that perturbs the helix in the 16S rRNA
a normal transpeptidase or penicillin-binding protein (PBP) is inactivated by penicillin, but penicillin no longer binds to the PBP with altered binding sites. This PBP is still able to carry out its cross-linking function so the beta lactam is no longer effective. what type of modification is this?
modification of the target
a terminal amino acid substitution that no longer allows vacomycin to bind is an example of what type of modification?
modification of the target
inactivation of an antibiotic by hydrolysis or by steric hinderance are examples of what type of modification?
antibiotic resistance by modification or inactivation of the antibiotic
what are the 3 antibiotic modifications that disrupt hydrogen-bonding network used to bind the 16S rRNA? what type of enzymes are used?
- N acetylation, O phosphorylation, and O adenylation
- aminoglycoside-inactivating enzymes
what are two prodrugs that bacterial resistance can be achieved against by modifying expression of bacterial factors needed to activate the antibiotic?
metronidazole and isoniazid
describe how resistance to isoniazid can be achieved by modifying expression of the bacterial factor needed to activate it
- isoniazid inhibits the synthesis of mycolic acids, required for the mycobacterial cell wall
- isoniazid is activated by the bacteral catalase/peroxidase enzyme KatG in mycobacterium tuberculosis
- modification of KatG will prevent activation of isoniazid, and mycolic acid synthesis will continue
metronidazole requires activation by ___ in H. pylori and P. gingivalis
flavodoxin
