There is concern that the efficacy of antibiotics against some bacteria species is dropping, with the drugs fast becoming practically useless. In this light, a new finding by a team at Princeton University should be exciting.
Resistant Gonorrhea
The researchers revealed in the journal Cell recently that they have discovered a compound that kills bacteria while leaving no room for resistance.
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The compound called SCH-79797 destroys both the walls and folate within bacterial cells while remaining immune to resistance. It is capable of getting rid of even highly resistant species, according to the researchers.
Antibiotic resistance is more of an issue with Gram-negative bacteria. These microbes have a robust outer layer that protects them against drugs.
Antibiotics capable of killing Gram-negative bacteria do not come to the market regularly – they take decades to develop. The latest class of such drugs made its appearance almost 30 years ago.
The Princeton scientists described SCH-79797 as the “first antibiotic” that can tackle both Gram-positive and Gram-negative bacteria.
Combating antibiotic resistance
A major challenge that scientists have to contend with when developing antibiotics is resistance. Bacteria can evolve quickly and render drugs that used to work previously ineffectual.
The development of antibiotics involves several things. In addition to searching for a molecule capable of killing bacteria, scientists also study how long it takes for resistance to set in. They breed the organisms for several bacteria generations, each lasting roughly 20 minutes, for their investigation.
Researchers typically use the information they have about how resistance occurs for reverse engineering. This enables them to know how a drug works.
The Princeton compound is an interesting one in that it allows no room for resistance. Researchers could not cause resistance to occur no matter how hard they tried.
The team went to the extent of using “brute force” to see if it would enable resistance to occur. Scientists exposed the microbes to the compound repeatedly for 25 days, even though a generation is only around 20 minutes long. Resistance failed to occur with SCH-79797, but it did when some other antibiotics were used.
As a result of the irresistibility observed, the Princeton team named the compound’s derivative “Irresistin.”
It is a good thing that SCH-79797 is irresistible to bacteria, but this creates another problem. The quality meant researchers could not reverse-engineer it to know how it works.
Arrow with a poisoned tip
The research team had to spend years trying to figure out how SCH-79797 kills bacteria due to its lack of resistance issues. A wide variety of techniques, including some dating to the early 20th Century, were used in an attempt to determine this.
What the researchers found was that the compound uses two approaches to kill bacteria. They compared its working to a combination of arrow and poison.
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The “arrow” destroys the tough outer layer of Gram-negative bacteria. On the other hand, the “poison” breaks down folate with the cells of the organisms.
Folate is crucial for RNA and DNA. It is a building block useful to both mammals, including humans, and microbes.
“The arrow has to be sharp to get the poison in, but the poison has to kill on its own, too,” said Benjamin Bratton, the first author of the study.
There are already drugs that use either of the two mechanisms of SCH-79797 for fighting bacteria, Bratton said. This new drug combines the two in one to deal more effectively with germs.
Eliminating highly-resistant species
Researchers in the current study compared their discovery to finding a formula that can turn lead to gold. James Martin, a recent Ph.D. graduate who worked extensively on the drug, initially found it somewhat hard to convince his colleagues that it kills bacteria without leaving room for resistance.
KC Huang, a professor of microbiology and immunology and of bioengineering at Stanford University, said the compound could be a game-changer in antibiotic development. He was not part of the study.
The researchers tested the drug against bacteria causing gonorrhea as well as some other resistant species. Neisseria gonorrhoeae is resistant to multiple antibiotics and the world is running out of potent drugs for the infection it causes.
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Using SCH-79797, the Princeton team was able to kill a highly resistant N. gonorrhea strain sample obtained from the World Health Organization (WHO). This particular strain is resistant to all antibiotics currently available.
“What used to be the last line of defense, the break-glass-in-case-of-emergency drug for Neisseria, is now the front-line standard of care, and there is no break-glass backup anymore,” said senior study author Zemer Gitai, the Edwin Grant Conklin Professor of Biology at Princeton. “That’s why this one is a particularly important and exciting one that we could cure.”
The original compound did not perform very well at differentiating human cells from bacterial cells. It killed both at about the same rate, meaning it could cause patients to die even faster.
To resolve this risk, the scientists made a derivative of SCH-79797 called Irresistin-16. This variant exhibited almost 1,000 times greater potency against germ cells than human cells.
The team was able to successfully treat mice having the N. gonorrhea bacteria using this derivative.
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Researchers say, while already very helpful by itself, Irresistin-16 could spur the discovery of other potent substances against resistant germs. It removes fear about potential harm to patients due to the targeting of processes existing in both humans and bacteria.
“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,'” said Gitai.
The researchers in the current study said the new drug showed “no detectable resistance.” They used this phrase and similar ones simply because it was not technically feasible to prove the negative.
References
Martin, J. K., 2nd, Sheehan, J. P., Bratton, B. P., Moore, G. M., Mateus, A., Li, S. H., Kim, H., Rabinowitz, J. D., Typas, A., Savitski, M. M., Wilson, M. Z., & Gitai, Z. (2020). A dual-mechanism antibiotic kills Gram-negative bacteria and avoids drug resistance. Cell, 181(7), 1518-1532.e14. https://doi.org/10.1016/j.cell.2020.05.005
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