In article <7mnqvg$120$1 at gxsn.com>, "Graham Shepherd" <muhero at globalnet.co.uk>
> Why these drugs work is a mystery to me; the sulfa combination is supposed
> to block folate metabolism in bacteria. Presumably we have an alternative
> pathway;
> I guess some protozoans don't have it and that makes them susceptible.
> If so, they would need to evolve the alternate pathway in order to become
> resistant.
> That sounds a lot more difficult than evolving a single enzyme like
> penicillinase.
> Anyone care to speculate on the probability?
Important point, they don't have to evolve an enzyme to break it down.
Three other ways to evolve resistance to such drugs come to mind.
First, export the drug back out of the cell. Gram negative bacteria
are thought to do this via a pump using tolC as one of its components.
Hiroshi Nikaido has published extensively on this. Certain tumors are
also known to develop multidrug resistance through use of an export pump.
It thus seems reasonable that protozoans could do so as well.
Second, reduce permeability to the drug. This is, admittedly, the
least likely as it involves reorganization of the membrane and thus
potentially many of the proteins in it. Still, Pseudomonas species are
known to do this in chronic lung infections.
Third, alter the enzyme target so it does not accept the drug in
question. I don't know how likely this is but it could be as simple as a
single amino acid substitution.
How big a problem this could be depends on how easily genetic
information is transferred between protozoans. For example, can they just
pick up a bit of extrachromosomal DNA from another species and transfer it
on like some bacteria? I have little knowledge of this. Does anyone care
to fill me in?
Exacerbating this problem is the fact that there are fewer alternatives
when treating eukaryotic infections. If resistance to one drug evolves in
bacteria, there are usually several alternatives. With eukaryotes, there
may not be.
Reflecting on Darwin's theory and the degree of evolutionary pressure,
I think the drug companies are going to be in business for quite some time
coming up with new antibiotics as old ones become less effective. I also
think we need to find ways to reduce their overuse.
Hope this helps,
D. Scott Snyder
