Antibiotics The March 1998 issue of Scientific American contains a good general article. The Challenge of antibiotic resistance by Stuart B. Levy.

The discovery of antibiotics [local] goes back to the 1920s, but scientists first started to get serious (i.e. get funding) about pursuing these molecules in the 1930s. At that time death from bacterial infections was common and almost everyone would have classmates die in school while growing up.

1940s brought WWII and governments became interested in antibiotics (i.e. large amounts of money became available). 1942 - penicillin introduced for clinical use [local], but remained in limited supply until the mid 1950s. 1944--spectromycin introduced. 1945--first penicillin resistant bacteria identified in hospitals. Since then it has been a contest to develop new antibiotics to keep ahead of bacterial resistance.

1990s--many pathogenic bacteria are resistant to all but one remaining available antibiotic. Staphylococcus (hospital infections), Pneumococcus (pneumonia) and Enterococcus (wound infections and meningitis) strains exist which are resistant to all antibiotics except vancomycin. Vancomycin resistance is present in other species and will soon be transferred to, or evolve in these bacteria.

Economics: It may take about $100,000,000 to develop and test a new antibiotic; it may take as little as three years for significant resistance to appear.

Stupidity: We use about 40% of the antibiotics we produce in agriculture to help keep food prices low. In Denmark in the year 1994 about 24 kg of vancomycin was used for human therapy, whereas 24,000 kg of avoparcin, a vancomycin analog, was used in animal feeds. Bacteria that develop resistance to avoparcin will also be resistant to vancomycin. See W. Witte (1998) Science 279: 996.

Most antibiotics work through one of three mechanisms.

A. Disrupt construction of bacterial cell wall, causing bacteria to become osmotically sensitive and burst (see it happen in this movie. Examples are the penicillins and cephalosporins. Penicillin is derived naturally from a cyclization of an L-cysteine-D-valine dipeptide. The 4 membered beta-lactam ring is essential for the inhibition of cell wall production. This ring is somewhat labile in aqueous solution and orally administered penicillins normally are 80% hydrolyzed in the stomach. Since cell wall synthesis occurs outside of the bacterial cell, these molecules do not have to enter the bacterium.

 

B. Inhibit bacterial protein synthesis. Because ribosomes and other procaryotic protein synthesis machinery are different from eucayrotic protein synthesis apparatus, specific inhibitors of the former can be produced. Because many steps are involved in protein synthesis, many different types of molecules can act as inhibitors. An example of this class of antibiotic would be puromycin, which mimics an aminoacyl-tRNA.

 

C. Inhibit DNA replication of RNA synthesis. These are usually molecules with aromatic rings which interchelate between the stacked bases in the DNA molecule. Example is actinomycin D or rifampin.

General strategies for resistance:

A: Mutate the cell wall or membrane components necessary for entry of the antibiotic into the cell.

B: Develop a pump to transport the antibiotic out of the cell.

C: Produce enzymes which destroy or modify the antibiotic.

D: Produce antibiotic binding proteins which lower the concentration of free antibiotic.

E: Make more of the target enzyme or molecule.

F: Mutate the target enzyme or molecule so that it is no longer sensitive to the antibiotic.

There is controversy in the scientific and public press recently about an antibacterial chemical called Triclosan.

This molecule is commonly found in consumer products such as soaps, toothpaste and acne medications. Some people are worried that it may act like an antibiotic and increase the incidence of antibiotic-resistant bacteria. This is being studied.