In the past seven decades, antibiotics and other antimicrobial agents have been extensively used to treat infectious diseases. Although antibiotics can be lifesaving drugs, they have often been found to be prescribed unnecessarily in incorrect dosages (or duration) 50% of the time. This has given rise to antimicrobial resistance (AMR) among disease-causing microorganisms which renders drugs ineffective.

Every year, 480,000 people worldwide develop drug-resistant tuberculosis. AMR is also becoming increasingly prevalent among HIV and malaria sufferers. Infections which are drug-resistant can be immensely challenging to treat, not to mention expensive. If AMR is not tackled effectively and quickly enough, “prolonged illness, disability, and death” are imminent, warns the World Health Organisation (WHO).

The answer lies in the genome

In a recent study published by Nature Communications, it was discovered that bacteria have more ways to defend themselves from the effects of antibiotics.

According to researchers from the Institute of Microbiology and Infection, University of Birmingham, certain protein in a gene called multiple antibiotic resistance (mar) is capable of providing resistance towards antibiotics by switching on other genes. Even though the existence of this gene has been known for decades, its modus operandi remains a mystery.

Escherichia coli. Photo credit: Rocky Mountain Laboratories,NIAID, NIH /
Escherichia coli. Photo credit: Rocky Mountain Laboratories,NIAID, NIH /

In order to uncover the exact functions of this gene, whole (entire) genome sequencing – a technique used to uncover the complete DNA make-up of an organism – was used on Escherichia coli in order to figure out its defence mechanism. It was a complicated process as resistance genes make up less than 1% of the entire genome sequence. However, the team was able to identify them through an advanced method called chromatin immunoprecipitation.

The genes were subsequently examined through experimental approaches, such as genetic manipulation of bacteria. Different antimicrobial agents were used on the bacteria to test for “hot spots” related to antibiotic resistance. It was found that the bacteria possessed a modified resistance towards two classes of antibiotics called tetracyclines and quinolones.

Deeper understanding of drug resistance mechanisms needed

Another interesting discovery mentioned in the study was that a modification process of the cell surfaces, and not mutation, was employed by bacteria to prevent antibiotics from “invading” them. It was further revealed that bacteria are capable of protecting their DNA by activating “molecular machines that repair DNA damage”.

"We found two completely unexpected mechanisms that bacteria use to protect themselves from antibiotics. One protected their DNA from the harmful effects of fluoroquinolone antibiotics, and the other prevented doxycyline getting inside bacteria," explained senior author David Grainger, a professor of molecular microbiology at the University of Birmingham.

The first author of the study, Dr Prateek Sharma, highlighted that the so-called resistance mechanisms can be found in different types of bacteria.

“Our research could lead to the discovery of molecules that could be developed into new drugs that can treat bacterial infections," he added.

Grainger hopes that further research on a particular protein called “multiple antibiotic resistance activator” will shed more light on the defence mechanisms used by bacteria against antibiotics. The development of antibiotics capable of disrupting bacterial defence systems, for instance, may prove useful to combat AMR in future. MIMS

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