Microorganisms—bacteria in particular—are skilled chemists who can make an impressive array of chemical compounds known as natural products. These metabolites offer great evolutionary advantages to microbes, for example enabling them to interact with each other or their environment and helping to defend against various threats. Because of the diverse functions that bacterial natural products serve, many have been used as medical treatments such as antibiotics and anti-cancer agents.

The microbial species alive today represent only a tiny fraction of the enormous diversity of microbes that have inhabited the earth over the past 3 billion years. Exploring this microbial past offers exciting opportunities to regain some of their lost chemistry.

Direct study of these metabolites in archaeological specimens is virtually impossible due to their poor preservation over time. However, their reconstruction using the genetic blueprints of long-dead microbes could offer a way forward.

We are a team of anthropologists, archaeogenetics and biochemists studying ancient microbes. By generating previously unknown chemical compounds from the reconstructed genomes of ancient bacteria, our newly published research provides a proof of concept for the potential use of fossil microbes as a source of new drugs.

The cellular machinery that produces bacterial natural products is encoded in genes that are typically in close proximity to each other, forming so-called biosynthetic gene clusters. Such genes are difficult to recognize and reconstruct from ancient DNA because very old genetic material degrades over time, breaking into thousands or even millions of pieces. The end result is numerous tiny fragments of DNA less than 50 nucleotides in length, all jumbled together like a jumbled jigsaw puzzle.

We sequenced billions of such ancient DNA fragments and then improved a bioinformatics process called de novo assembly to digitally organize the ancient DNA fragments into stretches of up to 100,000 nucleotides—a 2,000-fold improvement. This process allowed us to identify not only what genes were present, but also their arrangement in the genome and how they differ from bacterial genes known today—key information to uncover their evolutionary history and function.

This method gave us an unprecedented look at the genomes of microbes that lived up to 100,000 years ago, including species not known to exist today. Our findings push back the oldest reconstructed microbial genomes to date by more than 90,000 years.

In the microbial genomes we reconstructed from DNA extracted from ancient tartar, we found a gene cluster shared by a high proportion of Neanderthals and anatomically modern humans who lived during the Middle and Upper Paleolithic, 300,000 to 12,000 years ago . This cluster bore the molecular hallmarks of very old DNA and belonged to the bacterial genus Chlorobium, a group of green sulfur bacteria capable of photosynthesis.

We engineered a synthetic version of this gene cluster into a “modern” bacterium called Pseudomona protegens so that it can produce the chemical compounds encoded in the ancient genes. Using this method, we were able to isolate two previously unknown compounds, which we named paleofuran A and B, and determine their chemical structure. Re-synthesizing these molecules from scratch in the laboratory confirmed their structure and allowed us to produce larger quantities for further analysis.

By reconstructing these ancient connections, our results show how archaeological specimens could serve as new sources of natural products.

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

As recently as 25,000 to 10,000 years ago, the Earth underwent a major climate shift, transitioning from the colder and more volatile Pleistocene Epoch to the warmer and more temperate Holocene Epoch. Human lifestyles also changed dramatically during this transition as humans began to live outside of caves and increasingly experimented with food production. These changes exposed them to various microbes through farming, animal husbandry, and their newly built environments. Studying Pleistocene bacteria can provide insight into bacterial species and biosynthetic genes that are no longer associated with humans today, and perhaps even into microbes that have become extinct.

While the amount of data scientists are collecting about biological organisms has grown exponentially in recent decades, the number of new antibiotics has stagnated. This is especially problematic when bacteria can evade existing antibiotic treatments faster than researchers can develop new ones.

By reconstructing microbial genomes from archaeological specimens, scientists can unlock the hidden diversity of natural products that would otherwise have been lost over time, increasing the number of potential sources from which they can discover new medicines.

Our study has shown that it is possible to use natural products from the past. To unlock the vast variety of chemical compounds encoded in ancient DNA, we now need to streamline our methodology to be less labor intensive.

We are currently optimizing and automating our process to identify biosynthetic genes in ancient DNA faster and more reliably. We also implement robotic liquid handling systems to complete the time-consuming pipetting and bacteria culturing steps in our methods. Our goal is to extend the process to be able to translate a large amount of data on ancient microbes into the discovery of new therapeutics.

Although we can recreate ancient molecules, their biological and ecological roles remain elusive. Because the bacteria that originally produced these compounds no longer exist, we cannot culture or genetically manipulate them. Further studies must rely on similar bacteria that can be found today. Whether the functions of these compounds have remained the same in the 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 address the current antibiotic crisis by providing a new timeline for antibiotic discovery.

(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)


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