The kinds of bacteria that are resistant to all types of antibiotics are growing in number around the world, threatening to leave doctors of patients with infections increasingly unable to heal them. 

A new discovery by Tel Aviv University (TAU) researchers advances the future development of treatments against antibiotic-resistant bacteria. They discovered a process by which a “good” virus selectively destroys the DNA of “bad” bacteria, thereby stopping its reproduction.

The paper was recently published in the prestigious Proceedings of the [US} National Academy of Sciences (PNAS) under the title “A phage mechanism for selective nicking of dUMP-containing DNA.” 

The researchers showed that the “good” virus (called a “bacteriophage” because it “eats” bacteria) is able to block the replication mechanism of the bacteria’s DNA without damaging its own. Bacteriophages have co-evolved with bacteria for eons and have consequently developed mechanisms to specifically and optimally inhibit or divert key host metabolic functions. 

Increasing the knowledge about the bacterial pathways targeted by phages and identifying the disruptive gene products used against them may generate tools to manipulate bacteria. It is therefore important to examine strategies for identifying these interactions.

The team stressed that their discovery reveals one more fascinating aspect of the mutual relations between bacteria and bacteriophages and could lead to a better understanding of bacterial mechanisms for evading bacteriophages, as well as ways for using bacteriophages to combat bacteria. 

The study was led by Prof. Udi Qimron, Dr. Dor Salomon, Dr. Tridib Mahata and Shahar Molshanski-Mor of the TAU’s Sackler Faculty of Medicine. Other participants included Prof. Tal Pupko, head of the Shmunis School of Biomedicine and Cancer Research and also of the new AI and Data Science Center; Dr. Oren Avram of the Wise Faculty of Life Sciences; and Dr. Ido Yosef, Dr. Moran Goren, Dr. Miriam Kohen-Manor and Dr. Biswanath Jana of the Sackler Faculty of Medicine.

Qimron explained that the antibiotic resistance of bacteria is one of the greatest challenges faced by scientists today. One potential solution may lie in further investigation of the targeted eradication of bacteria by “good” bacteriophages that would overcome bacteria as a basis for the development of new tools to combat bacterial pathogens. 

With this intention, the team unveiled the mechanism by which the bacteriophage takes control of the bacteria. They found that a bacteriophage protein uses a DNA-repair protein in the bacteria to cunningly cut the bacteria’s DNA as it is being repaired. Since the bacteriophage’s own DNA has no need for this specific repair protein, it is protected from this “nicking” procedure. In this way the “good” bacteriophage does three important things – it distinguishes between its own DNA and that of the bacteria, destroys the bacteria’s genetic material and blocks the bacteria’s propagation and cell division.

“The bacteriophage takes advantage of the bacterial DNA’s need for repair, while the bacteriophage itself has no need for this specific kind of repair,” continued Qimron. “In this way, the bacteriophage destroys the bacteria without itself suffering any damage. The ability to distinguish between oneself and others is of enormous importance in nature and in various biological applications. So, for example, all antibiotic mechanisms identify and neutralize bacteria only, with minimal effect on human cells. Another example is our immune system, which is geared toward maximum damage to foreign factors, with minimal self-injury.”

The researchers discovered the process by searching for types of bacterial variants not impacted by this bacteriophage mechanism – those that have developed “immunity” to it. This led them to the specific bacterial mechanisms affected by the bacteriophage takeover. “We found that the ‘immune’ bacterial variants simply stopped repairing their DNA in ways that are vulnerable to the bacteriophage attack, thereby evading the bacteriophage’s destructive mechanism. Shedding more light on the ways in which bacteriophages attack bacteria, our findings may serve as a tool in the endless battle against antibiotic-resistant bacteria,” concluded Qimron.