Worrying discovery: Bacteria have a new way of developing antibiotic resistance

Bacterial resistance to all known antibiotics, including the so-called carbapenems, which are considered the last line of defense against these pathogens, are becoming a growing problem for public health.

According to a study published this year in the prestigious Lancet journal, bacterial infections have become the second leading cause of death in the world, and resistant bacteria already claim about 3,500 lives every day. Experts predict that by 2050, infections caused by resistant bacteria could kill about 10 million people a year, more than the number of deaths from cancer and diabetes combined.

Among the bacteria responsible for fatal drug-resistant infections, the top three are Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. These pathogens can cause dangerous infections in healthcare facilities in people with weakened immune systems.

The former adviser to the British government on health, Prof. Sally Davis warned back in 2013 that bacterial resistance poses a threat to humanity, like global warming or terrorism. Therefore, scientists are racing with bacteria and in that race they are trying to discover the secrets of the various mechanisms by which they acquire resistance.

Why do bacteria develop resistance so quickly?

Some of them have been known for years. Like all living organisms, bacteria constantly evolve to be able to fight off their rivals, predators and killers in their hosts and environment. They are very successful at this for several reasons.

One is that they multiply very quickly, so that in 20 minutes one bacteria can turn into two. It takes humans decades to reproduce. Moreover, they not only transmit their evolutionary adaptations vertically, to their offspring, but also exchange them horizontally – among themselves, regardless of species.

Namely, bacteria, which can be as different as humans and chickens, can exchange information about special properties, including resistance. This information is contained in so-called plasmids, small and easily mobile DNA molecules that are physically separated from the bacterial chromosomal DNA in the bacterial cells.

When two bacteria make physical contact, the donor bacterium will transfer the genetic material contained in the plasmid to the recipient bacterium via a thread called a pilus. This exchange, reminiscent of bacterial sex, is called conjugation. Since in conjugation the basic DNA of the bacteria does not have to undergo changes, it allows them to acquire resistance to antibiotics very quickly.

In addition, bacteria can possess several plasmids at the same time, which makes them very “powerful” in the fight against antibiotics. There is usually alarm in medical circles when it is discovered that some bacteria have stored their antibiotic resistance genes in plasmids, rather than just chromosomal DNA, because that means they can easily pass them on to other, perhaps more dangerous, bacteria.

A new mechanism for the development of resistance

Australian scientists recently published a paper in the journal Nature Communications in which they presented a previously unknown mechanism that allows bacteria to take in nutrients, the so-called folates, from their human host and bypass antibiotic treatment, ie. cancel the mechanism of action of the antibiotic.

They made this discovery while examining the antibiotic sensitivity of group A beta-hemolytic streptococcus – a potentially deadly bacterium that causes the most common bacterial throat infection as well as skin infections.

“Bacteria must make their own folic acid to grow and cause disease. “Some antibiotics work by blocking the production of folate to stop the growth of bacteria and treat the infection,” said study leader Timothy Barnett from the Wesfarmers Center of Vaccines and Infectious Diseases based at the Telethon Kids Institute in Perth, Australia.

“When we looked at an antibiotic commonly prescribed to treat skin infections caused by group A beta-hemolytic streptococcus, we discovered a resistance mechanism where, for the first time ever, the bacterium showed the ability to take folate directly from its human host when its own production was “blocked, rendering the antibiotic ineffective, and its use is likely to worsen the infection rather than reduce it,” Barnett explained.

“We suspect this is just the tip of the iceberg.”

Antibiotics targeting the folate biosynthesis pathway have been in development for over 80 years. For example, the antibiotic known as Sulfasol works in this way.

But Burnett points out that the newly discovered form of resistance cannot be detected under the conditions routinely used in pathology laboratories, making it difficult for doctors to prescribe antibiotics that will effectively treat the infection. This, in turn, can lead to very poor outcomes and even premature death.

“Unfortunately, we suspect this is only the tip of the iceberg – we have identified this mechanism in group A streptococcus, but it is likely to be a wider problem that exists in other bacterial pathogens,” said Dr Barnett.

Prim. Dr. Iva Butić, a specialist in clinical microbiology at the Dr. Fran Mihaljevic Infectious Diseases Clinic in Zagreb, Croatia, says this problem is likely to exist in all bacteria treated with antibiotics that target the folate pathway.

The team’s research found that understanding bacterial resistance is much more complex than previously thought.

Bacterial resistance is a bigger problem than the COVID-19 pandemic

Australian scientists point out that bacterial resistance to antibiotics poses a significantly greater risk to society than the COVID-19 pandemic. The World Health Organization estimates that resistance, in addition to claiming about 10 million lives a year, will cost the global economy about $100 trillion if new ways to combat it are not found.

“Without antibiotics, we face a world where there will be no way to stop deadly infections, cancer patients will not be able to receive chemotherapy, and people will not have access to life-saving surgeries. “To preserve the long-term efficacy of antibiotics, we must further identify and understand new mechanisms of antibiotic resistance, which will help discover new antibiotics and allow us to track resistance as it emerges,” Barnett said.

The first author of the new study, Calindu Rodrigo, announced that in the following studies he will focus his attention on the development of testing methods that should enable the detection of this type of antibiotic resistance in order to provide patients with effective treatment.

Butic points out that penicillin has proven to be the best antibiotic for treating infection with the bacteria mentioned in the paper.

“Since 1943, when penicillin was used clinically, group A streptococci have failed to develop resistance to it, which is considered a miracle,” says Butic.

It is important to develop rapid tests for this form of resistance

The authors of the new paper point out that in the context of increasing resistance, it is important to have new diagnostic tools that can rapidly detect it, including host-dependent resistance.

“Therefore, we hope to develop rapid point-of-care tests that can be used in remote settings where group A streptococcal infections are endemic,” said Rodrigo.

“It is important to stay one step ahead of the challenge of resistance, and as researchers we need to continue to investigate how resistance develops in pathogens and design rapid, accurate diagnostic methods and therapy.” On the other hand, equal efforts are needed at the level of society, including patients, health professionals and policy makers, in order to reduce the effects of resistance,” said Rodrigo.

In doing so, he recalled the fact that bacterial resistance contributes, among other things, to the irresponsible prescription of antibiotics when they are not necessary (for example, in the case of viral infections) and their irresponsible consumption (for example, premature discontinuation of therapy). , as well as ineffective, lower doses of antibiotics.