REHOVOT, Israel -- April 1, 1997 -- In a study that throws new light on the alarming phenomenon of increasing bacterial drug resistance, researchers at the Weizmann Institute of Science have discovered a molecule that enables bacteria to resist an unusually wide range of drugs. The finding, to be reported in the April issue of the Journal of Bacteriology (Vol. 172, #7, pp. 2274-2280), suggests it may become more and more difficult to design effective new medications for bacterial infections.
On the brighter side, the newly identified molecule, named MdfA, may serve as a model for the further study and understanding of multidrug resistance, aiding efforts to overcome this phenomenon in bacterial diseases. This research may also help clarify multidrug resistance in human cancers, which results in tumor cells expelling anti-cancer drugs, thus presenting serious obstacles to chemotherapy.
"The more sophisticated the drugs we develop, the more bacteria may emerge equipped with sophisticated ways to fight these drugs," says Dr. Eitan Bibi of the Institute's Biochemistry Department, who conducted the study with doctoral student Rotem Edgar. "This is an obvious challenge for antibacterial therapies that must be planned in anticipation of growing resistance mechanisms."
Dormant potential to survive
Cells of virtually all living organisms are known to contain molecules that enable them to resist a variety of substances. These molecules sit inside cell membranes and act as pumps, ejecting toxic compounds or other unwanted chemicals from the cell. However, the "unwanted" substances may include medications. Previously, most of these versatile molecular "pumps" were known to be capable of recognizing and resisting certain classes of drugs with particular chemical properties, such as those with a positive charge and a propensity to attach to lipids (molecules that make up cell membranes). These chemical properties determine how a drug will be absorbed by a cell, and influence the drug's toxic effects on a target site inside the cell.
The newly identified multidrug resistance molecule, MdfA, allows bacterial cells to expel one of the widest ranges known of unrelated antibiotics and other drugs, with widely varying chemical properties. For example, it can resist both positively charged drugs and those with no charge at all, as well as drugs that attach to lipids and those that do not.
"Finding a molecule with such an extraordinarily broad spectrum of resistance in one species of bacteria means we are likely to find similar molecules in other bacteria," says Bibi. "This highlights the dormant potential of some bacteria to survive even complex antibiotic treatments, and presents a challenge for future therapies."
An evolutionary advantage
Bibi and Edgar identified the MdfA molecule while researching multidrug resistance in Escherichia coli, a species of bacteria commonly used in scientific research. (E. coli normally live in the human colon and aid digestion, but if certain strains of the bacteria enter other organs through contaminated drinking water or improper toilet hygiene, they can cause serious illnesses such as acute infant diarrhea and urinary tract infections.)
The scientists conducted experiments in which they attacked the bacteria with various drugs. They found that MdfA was present and functional in low levels in all the E. coli strains they studied, and could fight off drugs administered in low amounts. Giving large amounts of combined drugs killed off most of the bacteria.
But when bacteria contained more than the usual amount of the mdfA gene, resulting in their producing much greater quantities of the MdfA molecule than normally, they survived even these harsh treatments. This suggests that the MdfA molecule is capable of conferring a high level of resistance to many unrelated drugs.
Bibi says evolution, given a push by modern medicine, seems to have played a role in the appearance of such broad-spectrum resistance molecules. Although modern medicines have undoubted and obvious benefits, a few bacteria have unavoidably survived each new drug because of natural resistance, and these have had an evolutionary advantage that they have passed on to their descendants. The result has been increasingly resistant bacteria, equipped with more versatile resistance mechanisms.
Dr. Eitan Bibi holds the Dr. Samuel O. Freedman Career Development Chair in the Life Sciences. Funding for this research came from the Israel Cancer Research Fund and from the Minerva Foundation of Munich, Germany.
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