Tightly knit communities of cells known as biofilms are a serious medical problem. In a biofilm state, bacteria are highly resistant to antibiotics and the host immune system.
They are a common reason why implanted medical devices eventually fail, and are speculated to be a common source of infections acquired in hospitals. How can bacterial biofilms be defeated?
Christian Melander (North Carolina State University, Raleigh) and coworkers have explored this challenge. They have synthesized a drug molecule that inhibits the formation of medically-important bacterial biofilms, and disrupts them after they have already been formed, in manner that is unlikely to be toxic to the patient.
Inspiration for and design of the drug molecule.
The design of the scientists' drug molecule was inspired by the chemical structure of a molecule known as bromoageliferin. This is a molecule that occurs in nature.
Scientists often synthesize chemical derivatives of molecules found in nature, in order to improve on the properties of the molecules. Other times, the intent is to impart entirely new properties on the molecules.
The scientists' initial inspiration led them to synthesize a molecule known as benzimidazole. This molecule possesses two rings comprised of carbon, nitrogen, and hydrogen atoms.
Chemical derivatives of benzimidazole find much use in synthetic chemistry, and are also present in nature. For example, a benzimidazole unit plays an important role in the structure and function of vitamin B12.
One chemical derivative of benzimidazole is 2-aminobenzimidazole. Chemical derivatives of the latter have also been investigated recently for a wide range of purposes.
These include those of pharmaceutical and energy importance, for example, insomnia and fuel cells. The latter are devices that convert chemical energy into electrical energy, and may become widely utilized in the future as environmentally-friendly sources of energy.
Most relevant for the research described herein, chemical derivatives of 2-aminobenzimidazole have been investigated recently for their antibiotic activity. Melander and coworkers have investigated their properties against bacterial biofilms.
Combating bacterial biofilms.
The scientists synthesized a series of chemical derivatives of 2-aminobenzimidazole for their studies. They unfortunately found that the molecules did not exhibit inhibition of gamma-proteobacteria biofilms, many of which are dangerous pathogens, such as those that cause typhoid fever and cholera.
They then studied the ability of their molecules to inhibit biofilm formation by other bacteria. Their choice was bacteria that are coated on the surface by a large amount of sugar-based polymers (known as Gram-positive bacteria).
Some of these bacteria are common bad guys in hospital-acquired infections. The scientists focused on three strains of bacteria: two strains of Staphylococcus (one of them drug-resistant), and one strain of drug-resistant Enterococcus.
They found that all of the potential drug molecules inhibited biofilm formation of at least two of these three bacterial strains. One drug molecule displayed an ability to both inhibit the formation of biofilms, and disrupt biofilms after formation, for all three bacterial strains, at low drug molecule concentrations.
Further experiments showed that none of the drug molecules killed the bacteria at molecular concentrations necessary to inhibit biofilm formation by 50%. This means that the biofilms are dispersed, but the bacteria live on.
This is a useful feature of an anti-biofilm drug. While additional antibiotics will be required to fully combat infections, the drug is less likely to be toxic, and possibly less likely to face the challenge of evolution-based drug resistance seen with so many other drug molecules that act instead by killing bacteria.
Basis of anti-biofilm activity.
The scientists next investigated the chemical basis whereby their most successful drug molecule combats bacterial biofilms. Such investigations are necessary for further improving upon the efficacy of initially successful drug molecules.
Iron and zinc ions are both important in the formation of biofilms of sugar-coated bacteria. The scientists thus tested the effect of these metal ions on the anti-biofilm activity of the drug molecule.
They found that while iron ions have no effect on the anti-biofilm capacity of their drug molecule, zinc ions do. This is most likely because the drug molecule chemically binds to zinc ions, which are required by many sugar-coated bacteria for physically attaching themselves to other bacteria, and subsequent biofilm formation.
Overall evaluation.
Melander and coworkers have developed a drug molecule that exhibits strong anti-biofilm activity against a medically-important class of bacteria, in a manner that does not kill the bacteria. This approach is unlikely to be toxic to the patient, and is also unlikely to face the challenge of drug resistance.
These features suggest that this preliminary drug molecule has a bright future towards improving the resilience of implanted medical devices, and combating what is thought to be a common source of hospital-acquired infections.
for more information:
Rogers, S. A., Huigens III, R. W., & Melander, C. (2009). A 2-Aminobenzimidazole That Inhibits and Disperses Gram-Positive Biofilms through a Zinc-Dependent Mechanism Journal of the American Chemical Society, 131 (29), 9868-9869 DOI: 10.1021/ja9024676