New Tool To Accelerate Search For Antibiotics Against Drug-Resistant Bacteria

Researchers from
Skoltech (a VEB.RF group institution) and other science
centers in Russia have developed a reporter system — a
tool for screening potential new antibiotics — that
enables the selection of drug compounds disrupting RNA
synthesis in gram-negative bacteria. Among others, these
include multidrug-resistant Pseudomonas aeruginosa
— a dangerous pathogen responsible for hospital-acquired
infections that has already adapted to existing antibiotics.
Targeting RNA synthesis is considered a promising mechanism
of action for new drugs, since few such agents are known and
used and therefore bacteria have not yet had a chance to
adapt to them. The study was
published in the International Journal of Molecular
Sciences and was supported by a Russian Science
Foundation grant.

Uncontrolled
antibiotic use drives the development of drug resistance in
bacteria. As a result, even previously harmless microbes
become dangerous. Pseudomonas aeruginosa, for
instance, is common in water and soil and readily colonises
the surfaces of medical equipment. Over the past 50 years,
it has successively acquired resistance to several classes
of antibiotics, making it a formidable cause of
hospital-acquired infections. Found on the skin of healthy
individuals, Staphylococcus aureus can nevertheless
cause pneumonia and other conditions when the immune system
is weakened. This bacterium, too, has adapted to several
antibiotics that used to kill it.

“One of the main
ways to combat antibiotic resistance is to search for new
active substances. An important step in studying new
compounds is determining their molecular mechanism of
action, which can subsequently help overcome bacterial
resistance,” explained the study’s principal
investigator, Assistant Professor Dmitrii
Lukianov from the Center for Biomedical
Technologies at Skoltech. “The reason why it is so
important to know the mechanism of action of each active
compound is that we can eventually study how that compound
works in detail and chemically modify it. You see, if a
bacterium has evolved resistance to one compound, this does
not automatically spell doom for all similar ones. Sometimes
we can tweak the molecule in a way that makes it potent
again.”

Skoltech researchers have presented an
improved tool for targeted screening of potential antibiotic
agents against gram-negative bacteria, such as
Pseudomonas aeruginosa. The new system is sensitive
to compounds that disrupt RNA biosynthesis — a process
essential to the life of bacterial cells. The search for
drugs that function in that particular way is considered
promising because pathogens have not yet had much exposure
to them. With relatively few such agents on the market —
primarily, rifampicin and fidaxomicin — the germs have not
had much opportunity to adapt.

The study’s lead
author, biologist Anton Izzi, described
what this search amounts to in practice: “Our colleagues
obtain an array of candidate compounds, among which a
promising antibiotic might be found, and send them to us for
screening. We then test them on bacteria in the lab. Well,
suppose a compound does kill the bacteria. That actually
happens a lot, but it’s not enough. We want to know why. A
compound might turn out to be toxic not just to bacteria but
to human cells, too. Or it may have a mechanism of action
that is common; so resistance to it will be relatively
widespread as well. This is where our reporter system comes
into play: It exposes the mechanism of action. If an
antibiotic targets ribosomes — as tetracycline does —
the system will show that. If it disrupts DNA synthesis —
as novobiocin does — we will know. Now that the toolkit
has been expanded, the new system can ‘see’ compounds
that inhibit RNA synthesis, as rifampicin does.”

The
new reporter system is based on a specially engineered
laboratory strain of Escherichia coli. The bacterium
carries a special gene that is expressed more strongly when
transcription — that is, RNA synthesis — is disrupted
compared with situations when other forms of stress are
experienced. This means that the gene becomes more active:
More messenger RNA is produced from it, which in turn serves
as a template for building a certain protein. The messenger
RNA is detected via the real-time polymerase chain reaction
method, and the system developed by the researchers then
signals that the compound in question inhibits RNA
synthesis.

Using the reporter system speeds up the
screening process and therefore improves the chances of
finding new drug molecules active against
antibiotic-resistant strains of dangerous pathogens. Without
such a system, the compound selection stage would require
researchers to examine the molecular structure of each
candidate, infer potential targets from it, and then verify
those targets — a considerable number of additional
tests.

Note:

Skoltech is a private
international university (part of the VEB.RF group) in
Russia, cultivating a new generation of leaders in
technology, science, and business. As a factory of
technologies, it conducts research in breakthrough fields
and promotes technological innovation to solve critical
problems that face Russia and the world. Skoltech focuses on
six priority areas: life sciences, health, and agro;
telecommunications, photonics, and quantum technologies;
artificial intelligence; advanced materials and engineering;
energy efficiency and the energy transition; and advanced
studies. Established in 2011 in collaboration with the
Massachusetts Institute of Technology (MIT), Skoltech was
listed among the world’s top 100 young universities by the
Nature Index in its both editions (2019, 2021). On
Research.com, the Institute ranks as Russian university No.
2 overall and No. 1 for genetics. In the recent SCImago
Institutions Rankings, Skoltech placed first nationwide for
computer
science.

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