EXAM 2 Antibiotic Resistance

Question 1

antibiotics are synthesized by ___ or ___

Answer 1

molds or bacteria

Question 2

naturally occurring antibiotics can be chemically modified to ___

Answer 2

improve/alter their activities

Question 3

in 1900 prior to antibiotics and vaccines, pneumonia, TB, diarrhea and enteritis, together with diphtheria caused ___ of all deaths

Answer 3

1/3

Question 4

___ was discovered by alexander fleming in st. mary’s hospital in london, september 1928. it was rediscovered by howard florey ___ years later.

Answer 4

• penicillin
• 10

Question 5

penicillin production was optimized in the US with the use of ___

Answer 5

new growth media and new molds

Question 6

how many additional antibiotics have been developed since penicillin was introduced?

Answer 6

over 140

Question 7

antibiotics save over ___ lives each year in the USA, adding ___ years to US life expectancy

Answer 7

• 200k
• 5-10

Question 8

which antibiotics target cell wall synthesis/integrity?

Answer 8

• beta lactams
• glycopeptides
• bacitracin
• fosfomycin

Question 9

which antibiotics target RNA synthesis?

Answer 9

rifampin

Question 10

which antibiotic targets amino-acyl tRNA synthetase?

Answer 10

mupirocin

Question 11

which antibiotics target folic acid (tetrahydrofolate) synthesis?

Answer 11

sulfonamides and trimethoprim

Question 12

which antibiotics target protein synthesis via the 30S ribosome?

Answer 12

aminoglycosides and tetracyclines

Question 13

which antibiotics target protein synthesis via the 50S ribosome?

Answer 13

• chloramphenicol
• macrolides
• lincosamides
• streptogramins
• everninomycin
• oxazolinonones
• lincosamides

Question 14

which antibiotics target DNA replication/repair/segregation?

Answer 14

• quinolones
• fluoroquinolones
• metronidazole

Question 15

over ___ million illnesses and ___ deaths are estimated to be as a result of antibiotic resistance

Answer 15

• 2 million
• 23,000

Question 16

if the current trend continues, antibiotic resistant bacteria are expected to cause the premature death of ___ million people per year globally by 2050

Question 17

___ is the rational, optimal use of antimicrobials

Answer 17

stewardship

all medical providers should behave as antimicrobial stewards

Question 18

what are the 4 major antimicrobial resistance mechanisms?

Answer 18

• 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)

Question 19

describe restricting antibiotic access as an antimicrobial resistance mechanism

Answer 19

• 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

Question 20

describe antibiotic resistance by modification of the target

Answer 20

• 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)

Question 21

describe antibiotic resistance by inactivation of the antibiotic: beta-lactamase

Answer 21

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

Question 22

describe antibiotic resistance by modification of the antibiotic: aminoglycoside-inactivating enzymes

Answer 22

• targets aminoglycosides
• modifications disrupt hydrogen-boning network used to bind 16S rRNA

Question 23

what are two ways resistance is acquired?

Answer 23

mutation and horizontal gene transfer

Question 24

which 3 ways can resistance genes be transferred?

Answer 24

conjugation, transformation, and transduction

Question 25

in e. coli, resistance to streptomycin can arise due to spontaneous mutation at a rate of 1 in a billion. why is this important?

Answer 25

though rare, the fast growth rates and high numbers of bacteria mean that rare events like this become meaningful

Question 26

what are 4 important classes of multidrug resistant bacterial pathogens that are becoming increasingly common?

Answer 26

* extended-spectrum beta lactamase producing enterobacteriaceae * carbapenem-resistant enterobacteriaceae * clostridium difficle * super neisseria gonorrhea

Question 27

describe extended-spectrum beta lactamase producing enterobacteriaceae

Answer 27

26,000 infections due to ESBL strains 1700 deaths per year $40k excess costs per infection

Question 28

describe carbapenem-resistant enterobacteriaceae

Answer 28

\>9000 healthcare associated infections are caused by CRE each year about 600 deaths due to resistant klebsiella and e. coli strains per year

Question 29

describe clostridium difficile

Answer 29

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

Question 30

describe super neisseria gonorrhea

Answer 30

246000 drug-resistant infections per year (30% of total gonococcal infections)

Question 31

what 4 things contribute to the selection and spread of multi-drug resistant strains?

Answer 31

overuse of antibiotics, overpopulation, poor hygiene, and travel

Question 32

the number of new antibiotics developed and approved has steadily decreased in the past 3 decades, leaving fewer options to treat resistant bacteria. why?

Answer 32

* development of new antibiotics is daunting: costs, pharmacokinetics, potential side effects * ideally target pathogens with minimal effects on beneficial microbiota

Question 33

describe antibiotic tolerance

Answer 33

* 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

Question 34

bacteria present within ___ are often protected from antibiotic treatments

Answer 34

biofilms

Question 35

\>\_\_\_% of human infections may involve biofilms

Answer 35

65

Question 36

biofilm formation enhances the ability of bacteria to tolerate antibiotics in what ways?

Answer 36

* extracellular matrix * altered protein expression * decreased metabolism * persister cell formation * increased genetic exchange * increased stress resistance

Question 37

what are persister cells?

Answer 37

dormant bacteria that are insensitive to many stresses and antibiotic treatments

Question 38

antibiotics have a hard time killing \_\_\_, but may still reduce bacterial numbers enough so that the host can regain control.

Answer 38

persisters

Question 39

describe bacterial resistance to tetracycline as an antibiotic resistance mechanism. what is the mechanism of resistance?

Answer 39

* 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

Question 40

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?

Answer 40

modification of the target

Question 41

a terminal amino acid substitution that no longer allows vacomycin to bind is an example of what type of modification?

Answer 41

modification of the target

Question 42

inactivation of an antibiotic by hydrolysis or by steric hinderance are examples of what type of modification?

Answer 42

antibiotic resistance by modification or inactivation of the antibiotic

Question 43

what are the 3 antibiotic modifications that disrupt hydrogen-bonding network used to bind the 16S rRNA? what type of enzymes are used?

Answer 43

* N acetylation, O phosphorylation, and O adenylation * aminoglycoside-inactivating enzymes

Question 44

what are two prodrugs that bacterial resistance can be achieved against by modifying expression of bacterial factors needed to activate the antibiotic?

Answer 44

metronidazole and isoniazid

Question 45

describe how resistance to isoniazid can be achieved by modifying expression of the bacterial factor needed to activate it

Answer 45

* 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

Question 46

metronidazole requires activation by ___ in H. pylori and P. gingivalis

Answer 46

flavodoxin