Resistance-free ‘poisoned arrow’ antibiotic kills Gram-negative bacteria

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A team of scientists from Princeton University (NJ, USA) have identified a ground-breaking antibiotic capable of killing Gram-negative and Gram-positive bacteria – all whilst avoiding antibiotic resistance. Their findings have been published in the journal Cell.

The novel compound, SCH-79797, acts as a ‘poisoned arrow’ – it can simultaneously puncture the bacterial cell wall and eradicate the folate within, leading to the death of the cell. Importantly, the antibiotic is effective against Gram-negative bacteria, which is notoriously difficult to target.

“This is the first antibiotic that can target Gram-positives and Gram-negatives without resistance,” commented Zemer Gitai (Princeton University), senior author on the paper. “From a ‘why it’s useful’ perspective, that’s the crux. But what we’re most excited about as scientists is something we’ve discovered about how this antibiotic works – attacking via two different mechanisms within one molecule – that we are hoping is generalizable, leading to better antibiotics – and new types of antibiotics – in the future.”

Discovering how this antibiotic functions was not an easy process. Typically, scientists would induce resistance in an antibiotic to reverse-engineer its mechanism of action. However, even after extraordinary effort, the team were unable to generate any resistance to this compound.

“This was a real technical feat,” commented Gitai. “No resistance is a plus from the usage side, but a challenge from the scientific side.”

After years of trying to determine the antibiotic’s method of action, the team eventually discovered that SCH-79797 uses two unique mechanisms: puncturing through the cell wall and additionally destroying folate – a building block for RNA and DNA. Surprisingly, the team found that these two mechanisms act synergistically.

“If you just take those two halves – there are commercially available drugs that can attack either of those two pathways – and you just dump them into the same pot, that doesn’t kill as effectively as our molecule, which has them joined together on the same body,” explained Benjamin Bratton (Lewis Sigler Institute for Integrative Genomics, Princeton University).

What’s more, a derivative of this antibiotic, Irresistin-16, was found to be 1000 times more potent against bacteria, allowing it to selectively target bacterial cells over human cells.

“This gives us a lot of hope, because there’s a whole class of targets that people have largely neglected because they thought, ‘Oh, I can’t target that, because then I would just kill the human as well,'” concluded Gitai.

Sources: Martin JK, Sheehan JP, Bratton BP et al., A dual-mechanism antibiotic kills Gram-negative bacteria and avoids drug resistance. Cell doi: 10.1016/j.cell.2020.05.005 (2020); www.eurekalert.org/pub_releases/2020-06/pu-ptd052820.php

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