A new way to restore antibiotic susceptibility in multidrug-resistant (MDR) Klebsiella pneumoniae and Escherichia coli strains has been discovered by researchers at the University of Copenhagen and Ross University School. Klebsiella pneumoniae is a main cause of fatal lung and bloodstream infections worldwide.

A novel approach to identify genes that are essential for these superbugs to grow in the presence of antibiotics was taken by the research team, led by Prof. Luca Guardabassi, DVM, Ph.D., from Copenhagen University.

Using cutting-edge technology in genomics, the researchers measured the contribution of every single bacterial gene to antibiotic resistance, leading to the identification of several genes that are vital for survival of MDR K. pneumoniae in the presence of colistin, the last resort antibiotic for treating infections caused by these bacteria. As a proof of principle, it was shown that inactivation of one of these genes, dedA, made colistin-resistant MDR K. pneumoniae completely sensitive to this antibiotic.

The same research team also discovered similar genes that upon inactivation restore susceptibility to beta-lactam antibiotics in MDR E. coli.

Reversing Antibiotic Resistance

The finding opens up new perspectives on the possibility to defeat resistant superbugs by combining antibiotics with ‘helper’ drugs that reverse antibiotic resistance. To date the β-lactamase inhibitors are the only type of antibiotic helper drugs used in clinical practice.

These drugs reverse antibiotic resistance by inhibiting the bacterial enzyme responsible for degradation of the β-lactam antibiotics. Differently from β-lactamase inhibitors, the targets identified by the researchers at the University of Copenhagen and Ross are not directly implicated in the mechanism of antibiotic resistance.

These targets are present in all bacteria, including susceptible strains, and thus can be used to indiscriminately potentiate antibiotic activity against both resistant and susceptible strains. Guardabassi, principal investigator in the project, said:

“In contrast to β-lactamase inhibitors, the antibiotic helper drugs conceptualized by our research would also improve efficacy of the ‘helped’ antibiotic against susceptible strains. This is a desirable feature for a helper drug as it would reduce the risk of treatment failure due to factors other than antibiotic resistance (e.g. biofilms, immunosuppression, etc.), allow dose reduction for toxic antibiotics such as colistin, and possibly even prevent selection of resistant mutants."

The latter hypothesis is presently under study using colistin in combination with an antifungal drug that is known to interfere with one of the targets identified by this research in MDR K. pneumoniae.

Multidrug-resistant Bacteria

Professor Anders Miki Bojesen, who coordinates the UC-Care research activities at the Department of Veterinary Clinical and Animal Sciences, said:

“It is extremely important to contain the threat posed by MDR bacteria. These new results create optimism for the future treatment of infectious diseases. Ahead of us now is the major task of exploring the potential of new drug targets, so that hopefully we can prevent the number of people with untreatable infections from escalating further."

Every year, more than 25,000 Europeans die as a result of infections caused by antibiotic-resistant bacteria. It has been estimated that in 2050 antibiotic resistance will cause 10 million deaths every year and as reduction of 2% to 3.5% in Gross Domestic Product globally.

MDR E. coli and K. pneumoniae are among the major contributors to the health and economic burden of antibiotic resistance on a global scale. Within the past 10 years, the prevalence of these resistant superbugs has increased worldwide. Of particular concern is the emergence of strains that have acquired resistance to carbapenems.

Due to the lack of any valid new therapeutic alternative, an older antibiotic, colistin, has become the last resort drug for managing infections caused by these superbugs. However, this antibiotic has toxic side effects and its use has selected for colistin-resistant mutants that are resistant to all antibiotics.

So the need to find alternative solutions is pressing, and the results of this new research are a promising break-through in the effort to defeat these resistant superbugs.

Bimal Jana et al The secondary resistome of multidrug-resistant Klebsiella pneumoniae Scientific Reports 7, Article number: 42483 (2017). DOI: 10.1038/srep42483

Baker KR, Sigurðardóttir HH, Jana B, Guardabassi L. 2017 Cephem potentiation by inactivation of nonessential genes involved in cell wall biogenesis of β-lactamase-producing Escherichia coli Antimicrob Agents Chemother 61:e01773-16. https://doi.org/10.1128/AAC.01773-16

Image: University of Copenhagen

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