Drug Resistance/Effectiveness of chemotherapeutic drug

Bacteria become resistant to chemotherapeutic agent by four major mechanisms:

1. Destruction or inactivation of the drug (by β- lactamase, for example)

2. Prevention of penetration to the target site within the microbe (a frequent mechanism for
tetracycline resistance)
3. Alteration of the drug’s target sites (for example, a single amino acid change in the ribosome may
be enough to make the microbes resistant to certain macrolide antibiotics)
4. rapid efflux (ejection), which pumps the drug out of the cell before it can become effective.

Variations on these mechanisms also occur. For example, a microbe could become resistant to
trimethoprim by synthesizing very large amounts of the enzyme against which the drug is targeted.
Conversely, polyene antibiotics can become less effective when resistant organisms produce smaller
amounts of the sterols against which the drug is effective.
Hereditary drug resistance is often carried by plasmids, or by small fragments of DNA called
transposons that can jump from one piece of DNA to another. Some plasmids, including those called
resistance ® factors, can be transferred between bacterial cells in a population and between different but
closely related bacterial populations. R factor contain genes for resistance to several antibiotics.
Strains of bacteria that are resistant to antibiotics are particularly common among people who
work in hospitals, where antibiotics are in constant use. Drugs should not be used indiscriminately, and the
concentrations administered should always be of optimum strength to minimize the chances of survival of
resistant mutants.
Another way to minimize the development of resistant strains is to administer two or more drugs
simuntaneously. If a strain is resistant to one of the drugs, the other might be effective against it. The
probability that the organisms will acquire resistance to both drugs is roughly the product of the two
individuals probabilities. However, multidrug-resistant tuberculosis is an emerging problem. Bacteria that
drugs are unable to control are the so-called superbugs.
There is a concern that the use of antimicrobials such as triclosan in soaps and other products may
promote the survival and growth of plasmid- carrying bacteria. These bacteria may also carry plasmids for
antibiotic resistance.

Effects of Combination of Drugs

The chemotherapeutic effect of two drugs given simuntaneously is sometimes greater than the effect of
either given alone. This phenomenon, called synergism, was introduced earlier. For example, in the
treatment of bacterial endocarditis, penicillin and streptomycin are much more effective when taken
together than when either drug is taken alone. Damage to bacterial cells walls by penicillin makes it easier
for streptomycin to enter.
Other combinations of drugs can show antagonism. For example, the simultaneous use of
penicillins and tetracycline is often less effective than when either drug is used alone. By stopping the
growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which
requires bacterial growth.

The Future of Chemotherapeutic Agents

Antimicrobial Peptides

Interest is now focusing on antibiotics produced by plants and animals often exhibit extraordinary
resistance to microbial infections. Multicellular animals, plants and insects are able to survive successfully
in a world full of potentially harmful microbes. Plants seeds survive and reproduce successfully in a soil
seething with bacteria and fungi. What plants, insects and many animals do have are powerful broad
spectrum antimicrobial peptides. More than 300 such peptides have been identified. The peptides form
disruptive channels in the plasma membrane, eventually killing the microbe. Resistant mutants do not seem
to have appeared in nature; apparently, this would require a complete and excessively difficult redesign of
the membrane.
Examples of antimicrobial peptides include magainin, which is found in the skin of certain frogs;
squalamine, an easily synthesized peptide found in the tissue of the spiny dogfish shark, and protegrins,
isolated from pigs. Several such peptides in advanced clinical trials.
Apparently, human skin and epithelial cells of the tongue and trachea also are sources of
antimicrobial peptides. Nisin, its use as a food preservative, resembles magainin in its mode of action on
membranes. It is the subject of considerable research to see whether nisin derivatives might replace
vancomycin for use against gram positive pathogens. Insects lack a mammalian type immune system and
produce an array of antimicrobial peptides to defend against infecting bacteria and fungi. One such
compound is cecropin, which is produced by certain moths.

Antisense Agents

Another promising new approach is the use of short synthetic strands of DNA, called antisense agents. The
principle is to identify sites on the DNA or RNA of the pathogen that are responsible for the pathogenic
effects. Segments of DNA are then synthesized that will selectively recognize and bind to the target site, a
process that blocks the biosynthesis of the target protein. This approach has great advantage: It prevents the
production of a pathogenic protein, rather than trying to selectively neutralize it once it is made. An
antiviral based upon antisense principles, fomivirsen, has been approved for treatment of the eye disease
cytomegalovirus retinitis.