Exploitation of free-radical producing pathway could also revive sidelined drugs.

Biomedical researchers at Boston University’s (BU) College of Engineering may have discovered the path toward developing drugs capable of defeating antibiotic-resistant bacteria, or superbugs. The team reports that they have found a previously unknown chain of events occurring in bacteria.

Currently, three classes of bactericidal antibiotics are used to target different bacterial functions: inhibiting DNA replication, blocking protein-building, or halting construction of cell walls. Research from the laboratory of James Collins found a common process that was triggered by all three types of antibiotics. 

This hidden pathway and resultant free radical overload appears to help current antibiotics do their job, but is not always enough to kill all bacteria by itself. Collins’ group theorizes that if this effect can be amplified, or if the cell’s genetic defense against it can be weakened, no bacteria could withstand its effect and the emergence of antibiotic-resistant bacteria could be limited.

“Importantly, we showed that if you can inhibit or block the bacterial defense mechanisms to hydroxyl radical damage, you can potentiate or enhance the lethality of bactericidal antibiotics,” explains Collins.

The BU team used DNA microarray studies to see if all three classes of bactericidal antibiotics triggered this process. Across the board, they noted increased gene activity along the intracellular assembly lines that make energy for the bacterial cell. They thus began to deduce the details of the new pathway.

Cells produce free superoxide radicals naturally in oxygen-rich environments. When they unnecessarily ramp up energy production such as when triggered by antibiotics, however, more radicals get churned out than the cell’s safety measures can mop up. The superoxide radicals then pull iron from other components of the cell, which rapidly stimulates production of toxic levels of hydroxyl radicals.

In addition to potentially making bacteria more vulnerable to current drugs, this finding may revitalize development of antibiotic drugs sidelined because of narrow differences between therapeutic and toxic doses, the investigators note. Such drugs might re-enter the pipeline, if this free-radical producing pathway is exploited to lower the therapeutic dose, making formerly dangerous drugs safer, they explain.

Collins and colleagues’ article appears in the September 7 issue of Cell.

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