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Researchers find a powerful potential weapon to overcome antibiotic resistance

  Researchers find a powerful potential weapon to overcome antibiotic resistance
Pseudomonas aeruginosa-produced rhamnolipids target the plasma membrane of Staphylococcus aureus (marked here in red) to increase the permeability of the aminoglycoside antibiotic. Points: Conlon Lab, UNC School of Medicine

Staphylococcus aureus bacteria are a major cause of serious infections that often persist despite antibiotic treatment, but researchers at the UNC School of Medicine have now discovered a way to make these bacteria much more susceptible to some common antibiotics.

The researchers found in a study published in Cell Chemical Biology that the addition of molecules called rhamnolipids can make aminoglycoside antibiotics, such as tobramycin, hundreds of times more potent against S. aureus ̵

1; including strains that are otherwise very difficult to kill. The rhamnolipids effectively detach the outer membranes of S. aureus cells so that aminoglycoside molecules can more easily enter them.

"There is a great need for new ways to kill bacteria that tolerate or resist standard antibiotics, and for this purpose we found that changing membrane permeability to induce aminoglycoside uptake is an extremely effective strategy against S. aureus "says study author Brian Conlon, Ph.D., assistant professor at the Department of Microbiology and Immunology at the UNC School of Medicine.

The United States Centers for Disease Control has estimated that in 2017 there were more than 119,000 cases of serious Staph infections in the United States, of which more than 20,000 were fatal.

Standard treatments for many strains of S. aureus do not kill the bacteria, either because the bacteria have genetically received specific antibiotic resistance or because they grow in the body in a way that makes them less vulnerable in itself. For example, S. aureus may adjust its metabolism to survive in low oxygen zones in abscesses or in mucous lungs of people with cystic fibrosis. In these environments, the outer wall or membrane of the bacterium becomes relatively impervious to aminoglycosides, such as tobramycin.

Conlon and colleagues, including first author Lauren Radlinski, a Ph.D. candidate in the Conlon laboratory, found in a 2017 study that rhamnolipids greatly improve the potency of tobramycin against standard test strains from S. aureus . Rhamnolipids are small molecules produced by another bacterial species, Pseudomonas aeruginosa, and are believed to be one of P. aeruginosa's natural weapons against other bacteria in nature. At high doses, they make holes in competing bacteria's cell membranes. UNC researchers found that rhamnolipids greatly increase the uptake of tobramycin molecules, even at low doses where they have no independent antibacterial effect.

In the new study, Conlon, Radlinski, and colleagues tested rhamnolipid-tobramycin combinations against S. aureus populations that are particularly difficult to kill in standard clinical practice. The researchers found that rhamnolipids increase the potency of tobramycin against:

  • S. aureus grows in low oxygen niches;
  • MRSA (methicillin resistant S. aureus ), which is a family of dangerous S. aureus variants with genetically acquired treatment resistance;
  • tobramycin resistant S. aureus strains isolated from cystic fibrosis patients;
  • and "Persist" forms of S. aureus which have normally reduced the sensitivity to antibiotics as they grow so slowly.

Radlinski said, "Tobramycin doses that would normally have little or no effect on these S. aureus populations killed them quickly when combined with rhamnolipids."

Conlon, Radlinski and colleagues also determined that rhamnolipids at low doses, S. aureus alters membranes in a way that makes it much more permeable to aminoglycosides. Every antibiotic in this family they tested – including tobramycin, gentamicin, amikacin, neomycin and kanamycin – had strengthened. The experiments also showed that this strength-enhancing strategy is effective not only against S. aureus but several other bacterial species, including Clostridioides difficile (C-diff), which is a major cause of severe, often fatal diarrheal disease among elderly and patients in hospitals.

Rhamnolipids are available in many variants, and scientists now hope to determine if there is an optimal variant that works powerfully against other bacteria while having little or no toxic effect on human cells. The team also plans to study other microbial vs microbial weapons to find new ways to improve the potency of existing antibiotics.

"There are a large number of bacterial interstitial interactions that can affect how well our antibiotics work," Radlinski said. "We strive to find them with the ultimate goal of improving the efficacy of current therapeutics and slowing the rise of antibiotic resistance."

Researchers find potential weapons for the fight against antibiotic resistance

More information:
Lauren C. Radlinski et al., Chemical Induction of Aminoglycoside Uptake Overcomes Antibiotic Tolerance and Resistance in Staphylococcus aureus, Cell Chemical Biology (2019). DOI: 10.1016 / j.chembiol.2019.07.009

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University of North Carolina Health Care

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Researchers find powerful potential weapons to overcome antibiotic resistance (2019, August 14)
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