A CHIP OFF THE OLD BLOCK Credit: ACS Infect. Dis.

Bacteria sometimes protect themselves from toxic molecules by actively pumping them out of their cytoplasm. This defense is often activated against antibiotics, rendering the microbes resistant to the drugs. A team of chemists now reports that supplementing a drug molecule with small fragments of itself could inhibit such efflux, offering a new route to designing therapies against resistant bacteria. The fragments act as molecular decoys that block the transport of larger drug molecules, the researchers say (ACS Infect. Dis. 2014, DOI: 10.1021/id500009f).

Bacterial efflux pumps target nearly all kinds of antimicrobial drugs. The proteins, scientists think, have binding sites for their specific molecules of choice—or small regions thereof. Once bound, the proteins pump the molecules out of the cells.

Jason K. Sello of Brown University and his colleagues set out to test whether a fragment of a larger drug molecule could bind to these pumps and block removal of the full molecules. They designed their tests around chunks of cyclic acyldepsipeptides (ADEPs), which are antibiotics that target microbes such as Mycobacterium tuberculosis.

They synthesized four fragments that each contain some of ADEP’s side chains to see which part of the molecule might be most effective at blocking efflux of the drug. They applied each fragment with the parent ADEP to plates of different strains of bacteria and determined which pair was the best at inhibiting microbial growth. The winning fragment included a fluorinated aromatic amino acid with a heptenoyl group.

The team then made small chemical changes to this fragment to increase its potency even further. When used against ADEP-resistant M. tuberculosis in a lab culture, the optimized fragment made ADEP two-and-a-half to five times more effective at inhibiting microbial growth than the antibiotic alone.

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The tests suggest that drug developers could mix antibiotics with fragments of those drugs to get around some forms of resistance. But the strategy needs to be tested further, including in animal models, according to Sello. He also needs to test whether other antibiotics are compatible with this approach. “A more structurally complex compound, such as erythromycin, for example, may not be as amenable to this fragment-based approach,” Sello says. Also, fragments of such complicated molecules may be tough to synthesize.

The study is an innovative approach to a very challenging problem, says Damian W. Young of Baylor College of Medicine. Combating resistant bacteria needs two approaches, he says: developing new drugs and making existing drugs more effective. One important way to increase the effectiveness of existing drugs is finding ways to let them hang around inside bacteria long enough for them to do their job.