A ‘Poisoned Arrow’ defeats Antibiotic-Resistant Bacteria

poisoned arrow antibiotic

Princeton researchers reported in the journal Cell that they have found a compound, SCH-79797, that can simultaneously puncture bacterial walls and destroy folate within their cells — while being immune to antibiotic resistance.

“This is the first antibiotic that is known to swiftly target Gram-Positive Bacteria and Gram-Negative Bacteria without resistance. From a ‘Why it’s useful’ perspective, that’s the crux. But what we’re most excited about as scientists are 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” said Zemer Gitai, Princeton’s Edwin Grant Conklin Professor of Biology and the senior author on the paper.

This compound looks like it’s the holy grail of antibiotic resistance drugs because of two reasons –  One, having the bacteria develop resistance to the drug but even after many efforts, the team found it impossible to generate resistance. The second was that it is the only antibiotic that is effective against diseases and immune to resistance while being safe in humans (unlike rubbing alcohol or bleach, which are irresistibly fatal to human cells and bacterial cells alike).

The only problem with the irresistible drug was that it couldn’t be reverse-engineered. Bacteria usually develop resistance towards the drug over the years and using that mechanism, scientists try to figure out the mechanism of the antibiotic. But since this antibiotic proved to kill off all forms of bacteria, they had nothing to reverse engineer it.

The scientists collected samples from the WHO and went back to the old school methods of testing, trying out various methods, right from classical techniques that help discover Penicillin, to the latest cutting technology advances. After seeing that nothing worked they named the compound’s derivatives as Irrestin because they were irresistible to anything.

In the end, they tried James Martin’s (a 2019 PhD graduate who spent most of his graduate career working on this compound) approach- “everything but the kitchen sink”, and it eventually revealed that SCH-79797 uses two distinct mechanisms within one molecule, like an arrow coated in poison.

“The arrow has to be sharp to get the poison in, but the poison has to kill on its own, too. It targets the outer membrane — piercing through even the thick armour of Gram-negative bacteria — while the poison shreds folate, a fundamental building block of RNA and DNA. The researchers were surprised to discover that the two mechanisms operate synergistically, combining into more than a sum of their parts. 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,” said Benjamin Bratton, an associate research scholar in molecular biology and a lecturer in the Lewis Sigler Institute for Integrative Genomics, who is the other co-first-author. But the only problem with this approach is that it can kill human patients faster than it can kill the bacteria, so it shall prove to be an ineffective cure.

Further research on how to find the reverse mechanism for the drug is still going on, as it still gives a ray of hope to be a promising target.

 

 

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