Antibiotics

Question 1

how can antibiotics enter cells?

Answer 1

1. Passive diffusion
   
   • antibiotic = lipophilic
   • crosses cell membrane of bacteria
   • Harder through gram -ve (2 membranes)
2. Active transport

Question 2

4 main mechanisms by which microorganisms exhibit resistance to antimicrobials

Answer 2

1. porins
2. pumps
3. metabolism
4. mutation

Question 3

what are porins?

Answer 3

channels

Question 4

how are porins used to help microorganisms exhibit resistance to antimicrobials?

Answer 4

Reduce drug access or drug accumulation by reducing drug permeability

Fewer pores = more resistant to antibiotics

Question 5

what is p-glycoprotein 1 also known as?

Answer 5

multidrug resistance protein 1, MDR1

ATP-binding cassette sub-family B member 1
ABCB1

cluster of differentiation 243, CD243

Question 6

what is p-glycoprotein?

Answer 6

a glycoprotein that in humans is encoded by ABCB1 gene and is a well characterised ABC transporter

Question 7

how are pumps used to help microorganisms exhibit resistance to antimicrobials?

Answer 7

Increase active efflux of the drugs across cell wall

Prevent therapeutic conc. from being achieved (= correct dose required)

If bacteria can pump out antibiotic, therapeutic concentration reached + target cell not killed

Question 8

how is metabolism used to help microorganisms exhibit resistance to antimicrobials?

Answer 8

Drug inactivation or modification

Hydrolysis of other amides/esters

Oxidative demethylation catalysed CYP450 also brings resistance
-OH, -NH, -SH (i.e. key alkyl groups)
removed via metabolism

Metabolise instead of pump -> via enzymes

Question 9

how are mutations used to help microorganisms exhibit resistance to antimicrobials?

Answer 9

Alteration of target site

increase no. of possible binding sites (dilute antibiotic effect)

alteration of biosynthetic pathways and biosynthetic requirements

Question 10

what is VRE?

Answer 10

[Vancomycin-resistant enterococci]

Bacterial strains of the genus Enterococcus

Question 11

how does Enterococcus become VRE?

Answer 11

vancomycin-sensitive enterococci obtain new DNA in the form of plasmids or transposons, which encode genes that confer vancomycin resistance

Question 12

where are VRE outbreaks most common?

Answer 12

hospitals

Can be carried by healthy people who have come into contact with the bacteria (most likely in hospital -> nosocomial infection; also some in factories)

Question 13

what are the 6 types of vancomycin resistance shown by enterococcus?

Answer 13

Van-A/B/C/D/E/F

Only Van-A/B/C have been seen in general clinical practice so far

Question 14

what is Van-A resistant to?

Answer 14

both vancomycin and teicoplanin

Question 15

what is Van-B resistant to?

Answer 15

Resistant to vancomycin

Sensitive to teicoplanin

Question 16

what is Van-C resistant to?

Answer 16

Partly resistant to vancomycin

Sensitive to teicoplanin

Question 17

what is Linezolid?

Answer 17

commonly used to treat VRE as teicoplanin is not available

Resistance within 2 years of discovery via 1 of 4 mechanisms

Question 18

Mechanism of resistance to vancomycin in Enterococcus

Answer 18

Alteration of the terminal amino acid residues of the NAM/NAG-peptide subunits

Under normal conditions, vancomycin binds to D-Alanyl-D-Alanine

Question 19

D-Alanyl-D-Alanine mutation

Answer 19

O for NH

Results in loss of 1 hydrogen-bonding interaction (4 instead of 5) being possible for vancomycin and new peptide (ester)

Loss of 1 points of interaction results in a 1000-fold decrease in affinity

Question 20

D-Ala-D-Ser variation

Answer 20

causes a 6-fold loss of affinity between vancomycin and peptide, likely due to steric hinderance

Question 21

what are the implications of vancomycin resistance?

Answer 21

Vancomycin = last antibiotic

When this is lost, we lose surgery in hospitals/transplants

= post antibiotic era

Question 22

what is Vaborbactam?

Answer 22

Potent broad-spectrum non-β-lactam β-lactamase inhibitor

Question 23

what is Vaborbactam used for?

Answer 23

Not effective as an antibiotic itself, it restores potency to existing antibiotics by inhibiting β-lactamase enzymes that would otherwise degrade them

When combined with an appropriate antibiotic, it can be used for the treatment of gram-negative bacterial infections

Question 24

Vaborbactam + carbapenem antibiotic combination

Answer 24

met all pre-specified primary endpoints in a phase 3 trial in patients with complicated urinary tract infections (cUTIs)

Question 25

serine carbapenemases

Answer 25

= family of β-lactamase enzymes

distinguished by their broad spectrum of activity and their ability to degrade carbapenem antibiotics

Question 26

what is serine carbapenemases used for?

Answer 26

treatment of multidrug-resistant gram-negative infections

Question 27

Vaborbactam specificity

Answer 27

higher affinity of human hydrolases for linear substrates similar to their endogenous substrates and low affinity for a cyclic boronate ester, like vaborbactam

Question 28

what are sulfonamides?

Answer 28

group of antibiotics

Question 29

what is MRSA?

Answer 29

resistant to penicillin

Question 30

how does the target cell prevent therapeutic conc. from being achieved?

Answer 30

makes copies of target

survive because they can make more resistant copies

NOT by altering target