A novel synthetic antibiotic can kill even drug-resistant bacteria

Antibiotic resistance is one of the major problems that pose a threat to the health of humans. Therefore, many studies have been conducted on the issue, and many scientists worldwide aim at putting an end to the crisis that kills more than a million people worldwide.

Scientists from Rockefeller University have synthesized a novel antibiotic with the help of computer models of bacterial gene products. It turns out to kill even bacteria resistant to other antibiotics. The molecule called cilagicin has been tested on mice, and it employs a new mechanism to attack MRSA, C. diff, and several other deadly pathogens.

“This isn’t just a cool new molecule, it’s a validation of a novel approach to drug discovery,” says Sean F. Brady, the Evnin Professor and the corresponding author of the study, in a press release published by the institution. “This study is an example of computational biology, genetic sequencing, and synthetic chemistry coming together to unlock the secrets of bacterial evolution.”

Bacterias killing each other

Since the evolution of bacteria consists of their invention of new methods to kill one another, it’s not surprising that most antibiotics are based on bacteria. However, bacteria's gaining resistance also leads to the emergence of such a problem as antibiotic-resistant bacteria, which gave rise to the need for new active compounds. 

However, countless antibiotics are probably hidden inside the genomes of stubborn bacteria that are difficult or impossible to examine in a lab. “Many antibiotics come from bacteria, but most bacteria can’t be grown in the lab,” Brady says. “It follows that we’re probably missing out on most antibiotics.”

For the past fifteen years, Brady's lab has adopted an alternative method that includes finding antibacterial genes in soil and growing them inside more lab-friendly bacteria. But this approach has its own limitations as well. The genetic sequences included in so-called biosynthetic gene clusters, which are groups of genes that work together to code for several proteins collectively, are where most antibiotics originate. But with present technology, those clusters are frequently inaccessible.

Unable to unlock many bacterial gene clusters, Brady and his colleagues turned to algorithms. Modern algorithms can anticipate the structure of the antibiotic-like compounds that a bacteria with these sequences would create by teasing apart the genetic instructions in a DNA sequence. And then, organic chemists can use the data and synthesize the predicted structure in the lab.

A promising compound

Zonggiang Wang and Bimal Koirala, postdoctoral colleagues from the Brady lab, started by working on a massive genetic-sequence database with the aim of finding potential bacterial genes that were believed to be important in killing other bacteria and hadn't been previously investigated. The "cil" gene cluster, which had not before been investigated in this context, stood out due to its proximity to other genes used in the production of antibiotics. Then the researchers duly fed its relevant sequences into an algorithm that proposed a handful of compounds that "cil" likely produces. One compound, appropriately named cilagicin, proved to be an effective antibiotic.

It turned out that Cilagicin functions by binding two molecules, C55-P and C55-PP, both of which support bacterial cell walls. Bacteria frequently develop resistance to existing antibiotics by cobbling together a cell wall with the remaining component. Drugs like bacitracin bind one of those two molecules but never both. So the team suspects that the capacity of cilagicin to shut down both molecules may actually be an insurmountable barrier that prevents resistance.

Though cilagicin has not undergone human testing yet, the Brady lab will carry out more syntheses to improve the compound in subsequent studies and test it in animal models against a wider range of infections to ascertain which diseases it would be most helpful in treating.

The results of the study have been published in the journal Science.

Abstract:
Emerging resistance to currently used antibiotics is a global public health crisis. Because most of the biosynthetic capacity within the bacterial kingdom has remained silent in previous antibiotic discovery efforts, uncharacterized biosynthetic gene clusters found in bacterial genome–sequencing studies remain an appealing source of antibiotics with distinctive modes of action. Here, we report the discovery of a naturally inspired lipopeptide antibiotic called cilagicin, which we chemically synthesized on the basis of a detailed bioinformatic analysis of the cil biosynthetic gene cluster. Cilagicin’s ability to sequester two distinct, indispensable undecaprenyl phosphates used in cell wall biosynthesis, together with the absence of detectable resistance in laboratory tests and among multidrug-resistant clinical isolates, makes it an appealing candidate for combating antibiotic-resistant pathogens.