Potential new antibiotics can be sourced from previously undiscovered molecules through the reconstruction of ancient bacterial genomes.

Microorganisms – especially bacteria – are skilled chemists who can produce an amazing variety of chemical compounds known as natural products. These metabolites provide microbes with key evolutionary advantages, such as allowing them to interact with each other or their environment and helping to defend against various threats. Because of the diverse functions of bacterial natural products, many have been They are used as medical treatments such as antibiotics and anti-cancer drugs.

The microbial species living today represent only a small part of the huge diversity of microbes that have inhabited the earth over the past three billion years. Exploring this microbial past offers exciting opportunities to recover some of its lost chemistry.

Direct study of these metabolites in archaeological samples is almost impossible because of them poor preservation over time. However, reconstructing them using the genetic blueprints of long-dead microbes could provide a way forward.

We are a team of AnthropologistsAnd Archaeologists And Biochemists who study ancient microbes. by to generate previously unknown chemical compounds From the reconstructed genomes of ancient bacteria, our newly published research provides proof of concept for the potential use of fossil microbes as a source of novel drugs.

Ancient genome reconstruction

The cellular machinery that produces normal bacterial products is encoded in genes that are normally in close proximity to each other, forming the so-called combinations of synthetic genes. Such genes are difficult to detect and reconstruct from ancient DNA because very old genetic material degrades over time, crumbling into thousands or even millions of pieces. The end result is many small DNA fragments Less than 50 nucleotides long All jumbled together like a jigsaw puzzle.

We sequenced the billions of these ancient DNA fragments and then improved a process called bioinformatics Assembly de novo to digitally arrange ancient DNA fragments into stretches of up to 100,000 nucleotides – a 2,000-fold improvement. This process allowed us to determine not only what genes are present, but also their order in the genome and the ways in which they differ from the bacterial genes known today—key information for revealing their evolutionary history and function.

This method allowed us to take an unprecedented look at the genomes of microbes that lived up to 100,000 years ago, including little-known species that exist today. Our findings pay off the oldest before Reconstructed microbial genome for more than 90,000 years.

In microbial genomes reconstructed from DNA extracted from ancient dental tartar, we found a gene cluster shared by a high proportion of Neanderthals and anatomically modern humans who lived during Middle and Upper Paleolithic that lasted from 300,000 to 12,000 years ago. I carried this block Molecular features of very ancient DNA It belongs to the bacterial genus chloropiuma group of green sulfur bacteria capable of photosynthesis.

We inserted a synthetic version of this gene pool into a “modern” bacterium called Pseudomonas proteins So it can produce the chemical compounds encoded in ancient genes. Using this method, we were able to isolate two previously unknown compounds that we named paleofuran A and B Determine its chemical composition. Recombining these molecules in the lab from scratch confirmed their structure and allowed us to produce larger quantities for further analysis.

By reconstructing these ancient compounds, our findings demonstrate how archaeological samples can serve as new sources of natural products.

Mining ancient natural products

Microbes are constantly evolving and adapting to their surroundings. Because the environments in which they live today are different from those in which their ancestors lived, microbes today are likely to produce different natural products than those of ancient microbes tens of thousands of years ago.

Recently like 25,000 to 10,000 years agoEarth has undergone a major climatic shift as it transitioned from colder and more volatile Pleistocene era to warmer to more temperate Holocene era. Human lifestyles also changed dramatically during this transition as people began living out of caves and increasingly experimented with food production. These changes brought them into contact with different microbes through agriculture, animal husbandry, and their new built environments. Studying Pleistocene bacteria may yield insights into bacterial species and biosynthetic genes no longer associated with humans today, and perhaps even microbes that have become extinct.

While the amount of data scientists have collected on organisms has increased dramatically over the past few decades, the number of new antibiotics has stagnated. This is particularly problematic when bacteria are able to evade current antibiotic treatments faster than researchers can develop new ones.

By reconstructing microbial genomes from archaeological samples, scientists can tap into the hidden diversity of natural products that would have been lost over time, increasing the number of potential sources from which they can discover new drugs.

Expanding the range of ancient molecules

Our study showed that it is possible to access natural products from the past. To take advantage of the huge diversity of chemical compounds encoded in ancient DNA, we now need to streamline our methodology to be less labor intensive.

We are currently improving and automating our process to more quickly and reliably identify biosynthetic genes in ancient DNA. We also implement automated liquid handling systems to complete the time-consuming pipette and bacterial cultivation steps in our methods. Our goal is to scale the process to be able to translate the huge amount of data on ancient microbes into the discovery of new therapeutic agents.

Although we can recreate ancient molecules, understanding their biological and ecological roles is difficult. Since the bacteria that originally produced these compounds are no longer present, we cannot grow them or genetically manipulate them. Further study will need to rely on similar bacteria that can be found today. Whether or not the functions of these compounds have remained the same in modern relatives of ancient microbes remains to be tested. Although the original functions of these compounds for ancient microbes may be unknown, they still have the potential to be repurposed to treat modern diseases.

Ultimately, we aim to shed new light on microbial evolution and combat the current antibiotic crisis by providing a new timeline for antibiotic discovery.

This article has been republished from Conversation Under Creative Commons Licence. Read the The original article.