Pilch - Mechanisms Of Drug Resistance

Question 1

Biochemical mechanisms of drug resistance

Answer 1

1) Decreased intracellular drug level
- there can be mutations that decrease the entry of the drug into the cell.
- There can also be a mutation can increase drug efflux out of the cell.

2) Increased inactivation of the drug
- bacteria can produce enzymes that render the antibiotics biologically inert.

3) Decreased conversion of a drug to a more active compound
- For instances sometimes we give drugs that only work once they are metabolized. But, if the drug isn’t being broken down as effectively then the drug won’t work.

4) Increased concentration of a metabolite that antagonizes drug action

5) Altered amount of target enzyme or receptor
- for instance, if the amount of target goes wayyyyy up, then you will need more antibiotic to kill off the bacteria. The issue though is that you have toxicity on the other end.

6) A mutation that causes decreased affinity of the receptor for the drug

7) Decreased activity of an enzyme required to express the drug effect
- alteration of an enzymatic process that is unaffected by the drug, but does not allow the drug to have its cytotoxic effect.

Question 2

Vancomycin resistance

Answer 2

Usually vancomycin binds to D-ala-D-ala and interferes with the formation of the PG matrix. An operon called VanHX produces enzymes that generate D-ala-D-lactate instead of our usual. Now, our PG matrix is still formed but vancomycin can’t recognize it.
- common in some enterococci

Question 3

Things to avoid when prescribing antibiotics to combat drug resistance

Answer 3

1) never give sub-inhibitory doses.
2) administer enough antibiotic to obtain clear killing or growth-inhibitory levels at the infection site.
3) administer combinations of drugs with different mechanisms of action.

Question 4

Strategies towards developing new antibiotics

Answer 4

1) combat bacterial resistance mechanisms
- develop inhibitors of drug-inactivating proteins and efflux transporters. Develop drug analogs that are resistant to drug-inactivating proteins
2) identification of new targets for therapy
- unique enzymes found only in infections organisms