Lecture 24 -- Antibiotics

Question 1

• streptomycete metabolites

- DNA gyrase is the target

Answer 1

coumarins

Question 2

• synthetic

- works against both gram negative and gram positive

Answer 2

quinolones

Question 3

which type of antibiotic functions by binding to DNA gyrase – it affects the double-stranded cleavage/double strand religation equilibrium

results in accumulation of doubly cut DNA-GyrA

Answer 3

quinolone

Question 4

• only used clinically as combination therapy
• RNA polymerase inhibitor
• only antibiotic in clinical use for blocking transcription

Answer 4

rifamycins

Question 5

what mechanism of action can bind the beta subunit of bacterial RNA polymerase at an allosteric site, preventing chain elongation

Answer 5

rifamycin

Question 6

• blocks a step in folic acid metabolism (folate synthesis)

- usually used in combination to achieve complete inhibition

Answer 6

sulfadrugs

Question 7

What role does tetrahydrofolate play in one carbon metabolism?

Answer 7

Donates or accepts carbon in:

• purine synthesis
• dTMP synthesis
• Amino acid metabolism

Question 8

which of the two tetrahydrofolate drug targets is slow killing, targeting the conversion of GTP to dihyropteroate

Answer 8

sulfamethoxazole

Question 9

which of the two tetrahydrofolate drug targets prevents recycling of THF to DHF, messing up the redox

Answer 9

Trimethoprim

Question 10

Using sulfamethoxazole along with trimethoprim results in a — fold increase in efficiency

Answer 10

100

Question 11

what type of enzymatic inhibition does sulfamethoxazole function through?

Answer 11

competitive inhibition

Question 12

what type of enzymatic inhibition does trimethoprim function through?

Answer 12

competitive inhibition

Question 13

List the four types of intrinsic antibiotic resistance

Answer 13

• cell wall impermeability
• efflux pumps
• inactivating enzymes
• alternative pathways

Question 14

List the three types of acquired antibiotic resistance mechanisms

Answer 14

• Point mutations
• Gene duplication/other alterations
• Gene transfer (efflux pumps/inactivating enzymes)

Question 15

Which type of mechanisms are inducible: intrinsic or acquired?

Answer 15

intrinsic; these bacteria are often antibiotic producers themselves

Question 16

What is the theory for how intrinsic antibiotic resistance mechanisms came about?

Answer 16

with the ability to synthesize antibiotics, resistance genes co-evolved to prevent antibiotic producers from committing suicide

Question 17

what genus/species produces most of the polyketide-based macrolide antibiotics

Answer 17

streptomycetes

Question 18

what are the three strategies for self-resistance in macrolide producers

Answer 18

• target modification
• expression of macrolide transport proteins
• macrolide inactivation

Question 19

how does target modification self-resistance work?

Answer 19

macrolides typically bind to the 23s rRNA, but these producers modify their 23s rRNA to prevent binding

Question 20

how does expression of macrolide transport protein self-resistance work?

Answer 20

the ABC transporter proteins (powered by ATP hydrolysis) pumps out macrolides

Question 21

how does macrolide inactivation self-resistance work?

Answer 21

at the end of the macrolide biosynthetic pathway, an enzyme modifies the molecule by adding a protective group (usually glucose)

OleB pumps out and OleR reactivates

Question 22

Why are the intrinsic methods of resistance not observed as a major route of resistance for antimicrobials (synthetic antibacterials)?

Answer 22

Bacteria have not been exposed to synthetic antibiotics for 100s of years (time is a factor)

Question 23

How can beta-lactams be inactivated and what are the two types of this enzyme that accomplish this (along with their differences)

Answer 23

• the b-lactam ring can be hydrolyzed (using beta-lactamases)
• serine beta-lactamases have an intermediate (Class A, C, and D)
• zinc beta-lactamases have no intermediate (Class B)

Question 24

what type antibiotics (producers) covalently modify the hydroxyl and amino groups of antibiotics to prevent binding to the 16s rRNA

Answer 24

aminoglycosides

Question 25

what type of antibiotics (producers) deactivate enzymes by opening the epoxide ring by adding glutathione – catalyzed by FosA

Answer 25

Fosfomycin

Question 26

what are efflux pumps often mediated by and do they move with or against concentration gradients

Answer 26

transmembrane proteins; against concentration gradients

Question 27

Are the majority of efflux pump families driven by PMF or ATP hydrolysis

Answer 27

PMF

Question 28

What three enzymes are involved in reprogramming the peptidoglycan termini and what are their functions

Answer 28

VanH and VanA are involved in converting pyruvate to lactate and D-ala-D-lac formation

VanX prevents the normal conversion of D-ala to D-ala-D-ala

Question 29

what antibiotic is overcome by the PG reprogramming

Answer 29

vancomycin; the signal for the expression of the Van series is received by a sensor kinase