New Compound 'Irresistin' Could Destroy Bacteria Without Causing Resistance: Study
Wed, April 21, 2021

New Compound 'Irresistin' Could Destroy Bacteria Without Causing Resistance: Study


A group of researchers has developed a novel compound that could kill bacteria and prevent resistance. The compound could pierce through the bacterial cell wall and destroy the folate within bacteria at the same time.

The novel compound for killing tough bacterial strains was developed by researchers at Princeton University, a private research university in the US. Their compound could puncture Gram-negative bacteria, known for having an armored cell wall. Upon penetration, the compound would destroy the folate inside to disable the ability of bacteria to synthesize nucleic acids. This compound was also found unable to trigger resistance development in bacteria. The findings were published in the journal Cell.

How Bacteria Can Counter the Effects of Antibiotics

Despite the therapeutic effects of antibiotics on bacterial infections, bacteria can evolve and develop ways to fight off these medications. These ways are called resistance mechanisms that often occur when a single bacterium survives a bombardment. The survivor carries a portion of the antibiotic used to kill its colony. Over time, the microbe's genetic processes utilize that portion to create new genetic instructions, which will result in resistance genes. These genes are usually stored in bacterial plasmids, and it means that the survivor can share it with other bacteria.

According to the US Centers for Disease Control and Prevention (CDC), a federal agency, the genetic evolution of bacteria against antibiotics can result in different resistance mechanisms. However, the most common ones are the ability to expel the toxic effects of antibiotics and the ability to improve cellular weak points. Other possible outcomes from the evolution include limiting the access points of antibiotics, pumping antibiotics out of the cell wall, altering or destroying antibiotics, changing the target of antibiotics, and bypassing the effects of antibiotics.

Many of these mechanisms are substantial in the outcome of a patient who has resistance. For example, if the bacterial strain possesses the ability to change the target of antibiotics, medications that can only target individual parts of the bacteria will likely be ineffective. Escherichia coli or E. coli with the mcr-1 gene can add one compound at the outer part of its cell wall to prevent colistin from attaching. This shows that even powerful antibiotics can be rendered useless even by the simplest strain of bacteria.



New Compound Kills Bacteria without Triggering Resistance

In medicine, bacterial infections are mainly differentiated through Gram staining, developed by bacteriologist Hans Christian Gram. Such infections can either be Gram-positive or Gram-negative. Aside from showing off distinct colors under a microscope, the test can tell what defensive traits the pathogen has. Between the two, Gram-negative bacteria are more resilient because their cell wall cannot be penetrated by antibodies. The same bacteria may also shrug off many classes of antibiotics.

At Princeton University, researchers developed a compound that might be the solution for superbug infections. The SCH-79797 could simultaneously pierce the bacterial cell wall and terminate the folate within while avoiding antibiotic resistance. This compound might comprise the first antibiotic for Gram-negative bacteria in almost 30 years. If one is made in the future, it could help millions of lives.

"This is the first antibiotic that can target Gram-positives and Gram-negatives without resistance. 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," said Zemer Gitai, the senior author of the study and professor of biology at Princeton.

In the study, the development of SCH-79797 was not the main obstacle. Researchers had to overcome two huge technical issues centered around resistance. First, they needed to prove that not one bacterium could resist. Second, they had to determine how the compound works, which could explain the irresistibility. For the resistance, the study's lead author James Martin conducted numerous assays and methods to show a particle of resistance to the compound.

Without results from those, he decided to go with brute force to uncover the resistance. For 25 days, he exposed bacteria samples to the compound several times. The samples could have millions of chances to develop resistance against it since bacteria tend to grow every 20 minutes in the lab, meaning the microbe had all the time to figure out a way to counter SCH-79797, yet none of the samples exhibited signs of resistance.

To confirm, researchers decided to go with other antibiotics, such as gentamicin, nisin, novobiocin, and trimethoprim. They exposed another set of bacteria samples to induce antibiotic resistance. These newly bred microbes were still no match against the compound. However, they could not accurately prove negative resistance. So, they categorized the status of resistance as either undetectably-low resistance frequencies or no detectable resistance. Tests showed that no detectable levels of resistance were found in the use of SCH-79797, which has been dubbed as Irresistin.



In the later phases of the study, among the top five urgent threats in antibiotic resistance, Neisseria gonorrhoeae was chosen by the team. The pathogen of gonorrhea has been deemed as a major headache in multidrug resistance. Because many of its strains already developed resistance to multiple antibiotics, the previous last resort became the first-line treatment. No antibiotic at present has been considered as the new final resort.

The N. gonorrhoeae sample was easily killed by the new compound. Researchers even obtained a sample from the most resistant strain of that bacteria, which could be found in the vaults of the World Health Organization. Irresistin also destroyed that strain without a problem. As such, the team labeled the compound as a poison-tipped arrow for bacteria.

Although the compound showed real promise in treating bacterial infections, the lack of resistance made it difficult to reverse engineer to reveal its mode of action. Fortunately, after years of investigation, they determined that Irresistin worked in two unique ways like a poison-coated arrow. The compound could target and pierce the outer membrane of Gram-negative bacteria. After that, it would destroy the folate inside. The two distinct ways showed that Irresistin could do what most antibiotics do all by itself.

According to the CDC's 2019 Antibiotic Resistance Threats Report, about 550,000 resistant gonorrhea infections occur in the US every year, but the total new infections each year, including non-resistant ones are 1.14 million. Those numbers are worth $133.4 million in terms of annual discounted lifetime direct medical costs. The resistance of N. gonorrhoeae developed so fast that it outpaced the speed of new drug development. In the 1980s, penicillin and tetracycline were no longer recommended for gonorrhea. By 2007, ciprofloxacin was removed from the recommended list of antibiotics, and by 2012, cefixime was erased from the first-line regimen of gonorrhea treatment.

Irresistin remains in the early stages of drug development. Its initial prototype is toxic to both bacterial and human cells, but researchers managed to formulate Irresistin-16 which is almost 1,000 more toxic to bacteria than human cells. The most recent application of the new formulation is in mice models, cured of gonorrhea.