Antibiotics are naturally occurring
substances made by certain bacteria and fungi (these
can be modified chemically, as well)
Antimetabolites are synthetic substances
made from chemicals by humans in factories
Discovery and development of early antimicrobial agents
Ehrlich (who
was also intrumental in early development of concepts about how the immune system functions)
synthesized salvarsan (effective against syphilis) in 1908
Fleming discovered
a mold that makes penicillin in 1929
Domagk synthesized prontosil and sulfanilamide in
1935
Florey and
Chain purified penicillin, demonstrated its effectiveness in treating
certain infectious diseases in 1941
Mechanisms of CTA action - CTAs work by
interfering with the synthesis or function of:
Metabolites - sulfonamides, trimethoprim,
and sulfones all block generation of metabolic
intermediates needed for generation of folic acid, a
vital growth factor neeed for thymidine synthesis
Membranes - amphotericin B, nystatin,
polymyxin B, imidazoles and triazoles all cause
disruption of membrane structure
Cell walls - penicillin, cephalosporin,
bacitracin, and vancomycin all interfere with
peptidoglycan synthesis; isoniazid (isonicotinic acid
hydrazide, INH) inhibits synthesis of mycolic acids,
which are part of the cell walls of mycobacteria
Proteins - erythromycin, streptomycin,
tetracycline, chloramphenicol all bind to ribosomes to
inhibit protein synthesis
Nucleic acids - naladixic acid, rifampin,
AZT, and acyclovir all interfere with nucleic acid
synthesis
Considerations for use of CTAs
Spectrum - indicates the variety of
microbes killed; broad-spectrum CTAs kill many
different microbes and may be preferred because of
this
Selective toxicity - a selectively toxic
agent is harmful to one living thing (e.g., microbe)
but not to another (e.g., host)
Effectiveness - CTAs must be administered
by an appropriate route so they can reach
infected sites in an appropriate
concentration to act against the organism(s)
within their spectrum
Susceptibility of microbe - microbial
resistance to a CTA acquired by via mutation or
acquisition of resistance genes (especially those
transmitted on plasmids) makes antibiotic sensitivity
testing of bacterial and fungal isolates from infected
persons very important for proper CTA therapy -
mechanisms
of resistance include:
permeability decreases - frequently due
to changes in membrane structure
export of CTA from microbe via active
transport mechanisms
target modification - changes in the
structure of the microbial protein, ribosome, etc.
that is affected by the CTA
CTA modification - examples of enzymatic
modification of CTAs include beta-lactamases (which
inactivate CTAs, such as penicillin, whose activity
depends on a beta-lactam ring and acetyl
transferases (which inactivate CTAs such as
chloramphenicol by adding acetyl groups to the
molecule)
Allergenic potential - the CTA must not
induce allergic (hypersensitivity) reactions in the
host because this can be uncomfortable, and might even
be life-threatening in some cases