antimicrobial therapy

goal of antimicrobial therapy

administer to an infected person a drug that destroys the infective agent without harming host cells

the perfect drug does not exist.

• must balance drug characteristics

• can achieve a compromise usually

microbicidal

kills microbes

microbistatic

stops growth of microbes

antimicrobial drugs should be selectively toxic, meaning;

drugs should kill or inhibit cells without simultaneously damaging host tissues

as the characteristics of the infectious agent become more similar to the vertebrate host cell,

complete selective toxicity becomes more difficult to achieve and more side effects are seen

types of antimicrobial drugs

• antibiotics

• synthetic drugs

• semisynthetic drugs

antibiotics

substances produced by natural metabolic process of certain microorganisms that can inhibit or destroy other microorganisms

• microbes do this to minimize competition for food and space

  • bacteria in genera Streptomyces and Bacillus

  • molds in genera Penicillium and Cephalosporium

synthetic drugs

made from completely chemical methods and dont involve microbes

semisynthetic drugs

improve natural antibiotics by tweaking them with chemical methods

origins of antimicrobial drugs

penicillin was discovered in 1929 and the first synthetic drug was discovered in 1935. many others have come since then

5 major useful drug targets in an actively dividing cell

1. inhibition if cell wall synthesis

2. breakdown of the cell membrane structure of function

3. interference with functions of DNA and RNA

4. inhibition of protein synthesis

5. blockage of key metabolic pathways

2 major groups that target cell wall synthesis

• beta-lactam antibiotics

• non-beta-lactam antimicrobials

beta-lactam antibiotics

(named for chemical structure)

• penicillins, cephalosporins and carbapenems block synthesis of peptidoglycan, causing the call wall to lyse

non-beta-lactam antimicrobials

• vancomycin

• bacitracin

• isoniazid (INH)

vancomycin

toxic to only used to treat staph infections that have penicillin or methicillin resistance or in patients with penicillin allergies

bacitracin

major ingredient in neosporin

isoniazid (INH)

interferes with synthesis of mycolic acid to useful in treating infections caused by acid-fast bacteria

antimicrobial drugs that disrupt cell membrane

a cell with a damaged membrane dies from disruption in metabolism or lysis

• these drugs specify for a particular microbial group, based on differences in types of lipids in their cell membranes

antimicrobial drugs that disrupt cell membrane

polymyxins interact with

phospholipids and cause leakage, particularly in gram-negative bacteria

antimicrobial drugs that disrupt cell membrane

amphotericin B and nystatin form

complexes with sterols in fungal membranes with causes leakage

antimicrobial drugs that affect nucleic acid synthesis (DNA and RNA)

may block synthesis of nucleotides, inhibit replication, or stop transcription

ex. chloroquine, quinolones, antiviral drugs that are analogs of purines and pyrimidines

antimicrobial drugs that affect nucleic acid synthesis

chloroquine

binds and cross-links the double helix

antimicrobial drugs that affect nucleic acid synthesis

quinolones

inhibit DNA helicases

antimicrobial drugs that affect nucleic acid synthesis

antiviral drugs that are analogs of purines and pyrimidines

insert in viral nucleic acid, preventing replication

antimicrobial drugs that block protein synthesis

ribosomes of eukaryotes differ in size and structure from prokaryotes; antimicrobials usually have a selective action against prokaryotes

ex. aminoglycosides, tetracyclines

antimicrobial drugs that block protein synthesis

aminoglycosides

insert on sites on the 30S subunit and cause misreading of mRNA

ex. streptomycin, gentamycin

antimicrobial drugs that block protein synthesis

tetracyclines

block attachment of tRNA on the A acceptor site and stop further synthesis

antimicrobial drugs that affect metabolic pathways

these drugs interfere with one or more metabolic pathways that help produce a specific product for the cell. lack of this product is generally harmful for the cell

antimicrobial drugs that affect metabolic pathways

sulfonamides, trimethoprim, retrovir act on metabolic pathways via

competitive inhibition

competitive inhibition

• drug competes with normal substrate for enzymes active site

• metabolic analog drugs are “dead-end” and cannot function as required

• as the enzyme is no longer able to produce a needed product, cellular metabolism slows or stops

synergistic effect

the effect of a combination of antibiotics are greater than the sum of the effects of the individual antibiotics

example of synergistic effect

sulfonamides and trimethoprim combined block enzymes required for tetrahydrofolate synthesis needed for DNA and RNA synthesis

major side effects of antibiotics

• direct damage to tissues through toxicity

• allergic reactions

• disruption in the balance of normal microbial flora

drug resistance

is an adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory

• result of genetic variability and adaptability of microbial populations

• can be intrinsic and acquired

main problem for microbial chemotherapy

acquisition of resistance

drug resistance is newly acquired after

1. spontaneous mutations in critical chromosomal genes

2. acquisition of new genes or sets of genes via transfer from another species

through intermicrobial transfer

• transfer of resistance factors encoded with drug resistance

• transposons duplicated and inserted from one plasmid to another or form a plasmid to the chromosome

mechanisms of acquired drug resistance

1. drug inactivation

2. decreased permeability

3. activation of drug pumps

4. change in drug binding site

5. use of alternate metabolic pathway

drug inactivation

inactivation of a drug that penicillin by penicillinase, an enzyme that cleaves a portion of the molecule and renders in inactive

decreased permeability

the receptor that transports the drug is altered, so that the drug cannot enter the cell

activation of drug pumps

specialized membrane proteins are activated and continually pump the drug out of the cell

change in drug binding site

binding site on target (ribosome) is altered so drug as no effect

use of alternate metabolic pathway

the drug has blocked the usual metabolic pathway, so the microbe circumvents it by using an alternative, unblocked pathway that achieves the required outcome

strategies to limit drug resistance of microbes

• physicians must make an accurate diagnosis and prescription

• patient must take the correct dosage for the appropriate period

• development of shorter-term, higher-dose antimicrobials that are more effective

• long-term strategies to reduce the abuse of antibiotics through education, justification for prescribing certain antibiotics

• restriction of use of antimicrobials in animal feed

• vaccines should be used whenever possible as alternative protection