Bacteria are resourceful microorganisms that are found throughout the world, surviving in some of the most extreme environments on the planet. The human body itself harbors about 1014 bacteria cells - about ten times more that the number of our own cells. Many of these so-called commensual microbes aid in digestion, removal of dead skin, toxin degradation and can even prevent infection by other microorganisms.

Unlike humans, bacteria are unicellular organisms. Each bacterial cell can function on its own, dividing to reproduce duplicate "daughter" cells.

Primary to the defenses of a bacteria are its complex outer structures: the "capsule", the "cell wall", and the "cytoplasmic membrane". It is these structures that first protect the bacteria from foreign compounds, like antibiotics.

In general, bacteria become resistant to antibiotics by using three major strategies. The first is to prevent the drug from reaching its target. Some bacteria accomplish this by having a "double-membrane" layer to retard the entry of the compound into the cell. Other bacteria simply expel the drugs from inside the cell using pumps located in the membrane.

The second strategy bacteria employ to become drug resistant is to produce enzymes that physically alter the antibiotic so that it can no longer bind to its cellular target. The third strategy is to physically alter the cellular target (the ribosome) so that an antibiotic can no longer bind and inhibit its function. Bacteria can use any combination of these methods to resist the action of antibiotics, rendering them therapeutically ineffective.

DNA mutations that allow bacteria to become antibiotic resistant occur as a natural consequence of the bacteria duplicating their DNA. Such mutations typically occur infrequently (10-5 to 10-7 per cell doubling), but because bacteria can reproduce every 20 minutes, mutations are much more common than in human cells. In addition to random mutation, bacteria are often able to exchange their DNA with one another thereby transferring resistance determinants, like efflux pumps, to their antibiotic sensitive neighbors. By employing these strategies, bacteria have virtually assured themselves of ways to develop resistance to the antibiotics in use today.

At Rib-X, we use our structure-based approach to understand how resistance to old and new antibiotic classes occurs at the molecular level. With this information, we can anticipate how resistance will develop in the future generations of bacteria and design workarounds that will maintain the therapeutic effectiveness of our novel compounds.