American Scientist

To the Editors:

Upon reading the article entitled "New Antibiotics and New Resistance," by Carlos Amábile-Cuevas, in the March– April issue, I felt there were other areas that needed highlighting, particularly nontraditional therapies. No new class of drugs with a novel mode of action has been discovered since nalidixic acid in 1962, suggesting that we must consider alternative methods for combatting antibiotic resistant bacteria. Areas of future interest include bacterial interference, development of antibacterial agents, and bacteriophage therapy.

Bacterial interference, or bacteriotherapy, is the practice of deliberately inoculating hosts with harmless bacteria to prevent infection by pathogenic strains. Pathogenesis is prevented because nonpathogenic bacteria compete with pathogenic bacteria for nutrients and adhesion receptors required for infection. However, parameters for the practical application of bacterial interference remain unknown.

Antibacterial agents refer to any natural or synthetic peptides that kill bacteria by destroying bacterial cell membranes. Examples of this strategy include the synthetic cell-membrane disruptors known as cyclic d,l-a-peptides. In contrast to any other known class of peptides, cyclic d,l-a-peptides can self-assemble into flat ring-shaped conformations to form a nanotube. Insertion of these self-assembled structures into the bacterial cell membrane causes holes that collapse transmembrane ion potentials and quickly kill the cell. These cyclic peptides possess a large "sequence space" that allows many structural changes without loss of function. Their targets and tube size can be easily altered through amino acid sequence and the number of residues. Consequently, they have been engineered to target bacterial membranes while excluding mammalian membranes.

Bacteriophage therapy uses viruses to specifically target and destroy bacteria. The strategy is quite attractive for several reasons. Phage particles are narrow-spectrum agents, meaning they target individual strains of toxic bacteria without harming other varieties. Furthermore, DNA manipulation of the phage genome allows the bacterial specificity to be changed, and since bacteriophages mutate in vivo just as easily as their bacterial targets, the therapy is more efficient.

Other ideas that are being piloted are oligosaccharide mimicking and antisense inhibition. The first is an anti-infective whereby oligosaccharides are designed to bind bacterial lipoproteins and glycolipids destined for bacterial attachment. The latter uses complementary oligonucleotides to target bacterial DNA, preventing viability.

Sean S. Kardar
Emory University
Atlanta, Georgia

To the Editors:

I just finished reading the excellent article "New Antibiotics and New Resistance." The author mentions a card game developed by his colleague Isabel Nivón-Bolán that illustrates mechanisms involved in acquiring and activating resistance to antibiotics. Can you tell me more about the game?

Shannon Barber
Yellowstone Elk Calf Project
Mammoth Hot Springs, Wyoming

Dr. Amábile-Cuevas replies:

I agree with Mr. Kardar that I did not mention a number of interesting options, mostly because of space limitations, but also because they were not within the scope of the article. Furthermore, only those research avenues that can be considered to be in the mainstream were mentioned (and, of course, some of our own work). Phage therapy and probiotics, although very interesting, are still in the realm of "alternative medicine." In any case, the active search of a wide variety of options is a clear indication of how desperately we need new ways to fight infections.

Probiotics, that is, live bacteria that are administered orally with the goal of preventing colonization by pathogenic bacteria, yield controversial results. For example, while probiotics prevent the colonization of the nose by pathogens (American Journal of Clinical Nutrition 2003; 77:517–520), they were unable to prevent the recurrence of a gut condition caused by colonizing bacteria (Gut 2002; 51:405-409).The issue was also reviewed in Trends in Microbiology (2001; 9:424–428). In any case, the absolute absence of resistance genes (not only of resistance phenotypes) in such bacteria must be demonstrated to prevent the mobilization of resistance traits to pathogenic germs. And it is so far intended as a preventive measure, not as therapy.

Phage therapy was extensively explored in the former Soviet Union. However, the spectrum of phages is so narrow that it may preclude their clinical use: Phages are often so specific that they infect only certain strains of a bacterial species. Furthermore, adding more mobile genetic elements into the equation might have unpredictable consequences; in some natural environments, such as seawater, phages are perhaps the main vehicle for gene transfer, an activity we would not like to increase within a patient. A recent review on phage therapy was published elsewhere (Antimicrobial Agents of Chemotherapy 2001; 45:649–659).

The increase in antibiotic resistance is fostering research in many ways. New drugs or even new strategies are certainly needed, but perhaps more important is the need to avoid the abuses and mistakes of the "antibiotic era." Much more than the effect of new agents against bacteria in vitro or in a handful of treated patients, it is necessary to look at the big picture before unleashing any other product of our genius.

As for the game: Isabel Nivón-Bolán headed a team here at Fundación Lusara that developed a card game ("Bugs & Drugs," she called it) as an educational tool for understanding antibiotic resistance evolution in a dynamic and amusing way. In addition to the great danger that antibiotic resistance poses to public health, it is a super example of biological evolution through natural (or not-so-natural) selection. We are happy to provide on our Web site (www.lusara.org) files that individuals can download and use to produce their own game by printing on pre-cut cards.

The game tries to represent the random factors and competitive processes through which genes are exchanged, resistance is gained and antibiotics select resistant organisms. Each player becomes a type of bacterium, which may gain resistance genes or suffer the effects of antibiotics while struggling to survive and reproduce. In addition to "classic" resistance genes, which are gained by mutation or gene transfer, this game includes more recently discovered resistance mechanisms such as activable resistance phenotypes, and even antibiotic "persistence" gained by growing in a biofilm.