Scientists discover how resistant bacteria block entrance of antibiotics

By Lois Zoppi, B.A.Sep 2 2019Reviewed by Kate Anderton, B.Sc. (Editor)

Scientists have discovered how a bacterium that can cause fatal hospital infections evolves to become resistant to antibiotics. The research, carried out by scientists at Imperial College London, has shown that the bacteria close small ‘doors’ in their cell walls to protect themselves against antibiotics in order to continue proliferating in a number of dangerous types of infections.

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Published in Nature Communications, this new discovery could lead to the development of new drugs that can open these cell wall doors and allow antibiotics inside bacterial cells.

The bacteria investigated in the study is Klebsiella pneumoniae, which is responsible for causing infections in the lungs, bloodstream, and in wounds or surgical sites, along with urinary tract infections and meningitis.

Hospital patients and those with compromised immune systems are particularly at risk of contracting infections from this type of bacteria, which can be fatal.

‘A serious threat to public health’

With over 20,000 K. pneumoniae infections in UK recorded over the last year, the increasing resistance to antibiotics K. pneumoniae is developing is particularly concerning, and a particular family of drugs, Carbapenems, are becoming less and less effective against the bacteria.

Carbapenems are used when other types of antibiotics have not successfully treated a patient’s infection, and if they are not able to fight infections due to resistance from bacteria, the ability to fight infections overall is greatly reduced.

A separate study titled “An Overview of Carbapenem-Resistant Klebsiella Pneumoniae: Epidemiology and Control Measures” states “The emergency and dissemination of carbapenem resistance among Enterobacteriaceae, especially Klebsiella pneumoniae, constitute a serious threat to public health, since carbapenems are the agents of last resort in the treatment of life-threatening infections caused by drug-resistant Enterobacteriaceae.”

The prevalence of antibiotic resistance is increasing, so we are becoming more and more reliant on drugs like Carbapenems that work against a wide range of bacteria. But now with important bacteria like K. pneumoniae gaining resistance to Carbapenems it’s important we understand how they are able to achieve this.”

Dr. Joshua Wong, First Author

The World Health Organization (WHO) have classed the Carbapenem resistant K. pneumoniae as “critical” Priority 1 organisms, illustrating the level of risk surrounding this issue.

Wong said that their new study “provides vital insights that could allow new strategies and drugs to be designed.”

Closing the door on antibiotics

For the study, the researchers compared the structures of Carbapenem-resistant K. pneumoniae bacteria and bacteria that had not yet built up any defense against the drug.

They discovered that the resistant bacteria had modified versions of a protein responsible for making the cell wall porous. They also found that resistant bacterial cells could lack this protein altogether.

The modified or missing protein lead to the pores on the cell wall being much smaller than usual, making it impossible for drugs to enter the bacterial cell.

While this is problematic for antibiotics, the small pores also mean the bacterial cells are unable to grow quickly as they are able to absorb fewer nutrients.

“The modification the bacteria use to avoid antibiotics is difficult to get around,” Professor Gad Frankel of the Department of Life Sciences at Imperial College London and leader of the research said. “Any drugs to counteract this defence mechanism would likely also get blocked out by the closed doors.”

“However, we hope that it will be possible to design drugs that can pick the lock of the door, and our data provides information to help scientists and pharmaceutical companies make these new agents a reality.”

The widespread use of Carbapenems in hospitals is believed to be driving the spread of dangerous superbugs, and this new study provides a scientific foundation from which to develop new strategies to fight this particular type of antibiotic resistance.

The research team is all part of the Antimicrobial Research Collaborative at Imperial College London, which is a multidisciplinary center focusing on antibiotic resistance and advancing research, new prevention strategies, and healthcare interventions, and informing policies on public health.

In this case, the authors suggest restrictive prescribing policies that limit the use of drugs with broad-spectrum activity like Carbapenems.