Researchers target antibiotic resistance

Antibiotics that don’t kill bacteria. Vaccines that don’t produce antibodies. Agents that prove their efficacy by producing no proven effects.

In the alarming new world of antibiotic resistance, researchers around the world are turning received wisdom on its head. In the race to save humans and animals – quite literally – scientists are abandoning traditional approaches to defeat infection with deadly force, acknowledging that approach has been exhausted.

Researchers met this week in Kansas City, Mo., at a symposium titled “Antibiotics: Choosing the Path of Least Resistance.” The event was presented by the Kansas City Area Life Sciences Institute, the KC Animal Health Corridor, and the veterinary schools of the University of Missouri and Kansas State University.

Because many pathogenic bacteria adapt to attempts to kill or injure them, researchers are looking at anti-infective strategies that block their function or pre-empt colonization altogether. Though much of their work is in early stages, the range of measures they are exploring suggests radical departures from the past and broad directions for the future.

Susan Egan, Ph.D., chairperson of the Department of Molecular Biosciences at the University of Kansas, is one researcher striking out in a new direction. To block bacteria’s function, her team is targeting virulence factors that control such actions as attachment, cell invasion, and toxins.

However, because a bacterium can easily adapt by developing alternative virulence strategies and altering its antigens, Egan’s work begins one level deeper: the control of virulence factors.

Transcriptional activator proteins (particularly those in the AraC family) often regulate the expression of many virulence factors. These proteins are nonessential – that is, the proteins are not necessary to the bacterium’s survival. Egan's team anticipates that an antibiotic operating at this level could turn off the virulence activators in stealth mode.

Or, as Egan and colleagues explain, “inhibition of AraC family virulence activators is expected to exert less selective pressure on bacteria to develop resistance than currently available antibiotics.”

Focusing on Shigella flexneri, Egan’s team used a small-molecule compound called SE-1 to block expression of VirF, which is required for the expression of the bacteria’s virulence genes associated with invasion and cell-to-cell spread of the bacterium. Their conclusion: SE-1 has “the potential to be developed into a novel antibacterial agent.”

If the theory pans out, it could give rise to a new class of antibiotics ... someday. And, the approach may have other possible benefits. Gene suppression may be useful in preventing bacteria in the gut from expressing genes that interfere with the effectiveness of therapeutic drugs in some individuals, according to Laura Cox, Ph.D., a postdoctoral fellow in the laboratory of Dr. Martin Blaser at NYU Langone Medical Center.

That would give a boost to existing some existing drugs, while better solutions move from laboratory to clinic.

Next week in NEWStat: Vaccines that target injection nanomachines, from the Kansas City Animal Life Sciences Institute’s symposium: Antibiotics: Taking the Path of Least Resistance.


AAFP/AAHA Basic Guidelines of Judicious Therapeutic Use of Antimicrobials (Revised January 2014) 

Layman’s guide to antibacterial resistance

Rise of the Superbug - Antibiotic-Resistant Bacteria

Dr. Karl Klose at TEDxSanAntonio

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