Researchers develop two new antibiotics that do not trigger resistance in mice

Professor Brice Felden and his team at INSERM and the University of Rennes 1 have created two new antibiotics effective not only against Gram positive and negative multiresistant bacteria, but they also do not appear to trigger resistance when they are used to treat an infection in mice. This breakthrough could offer new opportunities to fight antibiotic resistance worldwide. The details of this research are published in PLOS Biology.

Antibiotics are considered one of the major breakthroughs in contemporary medicine. Unfortunately, their increasing resistance makes them progressively ineffective, with the risk of catastrophic consequences for public health if this trend continues much longer. The few new antibiotics put on the market each year are basically so-called "me-too drugs", which means that they are derived from existing antibiotic classes.

Researchers from INSERM and the University of Rennes have recently identified a new bacterial toxin that they have turned into potent antibiotics active against bacteria responsible for human infections, Gram-positive or negative. "It all started with a fundamental discovery in 2011," says Brice Felden, director of the RNA and bacterium research laboratory in Rennes. "We realized that a toxin produced by Staphylococcus aureus, whose role is to facilitate the infection, is also able to kill other bacteria present in the body. What we had identified was a molecule that was both toxic and antibiotic. We thought that if we could separate these activities, we could create a new non-toxic antibiotic for the body – a challenge we accepted. "

In collaboration with the team Michèle Baudy Floc & h, chemist at ISCR, a new family of peptidomimetics was synthesized. As their name suggests, these peptides are inspired by existing natural bacterial peptides, but have been shortened and modified. Of the 20 molecules created, two proved to be effective against the resistant ones. Staphylococcus aureus and Pseudomonas aeruginosa in murine models of severe sepsis or skin infection. In addition, no toxicity to other cells and organs, either in animals or in humans, has been observed.

These new compounds are well tolerated at their active doses – and even beyond – and are free of the problems of renal toxicity often encountered with this type of compound. "We tested them at doses 10 to 50 times higher than the effective dose without observing the toxicity," says Felden. "The participation and imagination of the team and our chemistry colleagues were needed to design the most active molecules possible."

Little resistance observed under experimental conditions

In particular, the bacteria showed no signs of resistance after several days of in vivo drug exposure. To go further, researchers have created favorable conditions for the development of resistance in vitro and in vivo – without result. However, they are cautious about these results, given the short experimental periods (up to 15 days).

The antibacterial activity of these peptidomimetics is partly due to the ability of their unnatural amino acids to enhance the association of these compounds with the membranes of the infectious bacterium. This strong bond causes permeability of the membrane and death of the bacteria.

"We believe these new molecules represent promising candidates for the development of new antibiotics that can provide alternative treatments for antimicrobial resistance." The next step is to launch Phase I clinical trials in humans.

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