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Making Resistant Superbugs Sensitive to Antibiotics

Researchers find new way to restore antibiotic susceptibility in K. pneumoniae and E. coli strains

Researchers at the University of Copenhagen have discovered a new way to restore antibiotic susceptibility in multidrug-resistant (MDR) Klebsiella pneumoniae and Escherichia coli strains. The promising findings were published in two journals, Scientific Reports and Antimicrobial Agents and Chemotherapy.

The researchers measured the contribution of every bacterial gene to antibiotic resistance, leading to the identification of several genes that are vital for the survival of MDR K. pneumoniae in the presence of colistin, the last-resort antibiotic for treating infections caused by these bacteria. The scientists found that inactivation of one of these genes, dedA, made colistin-resistant MDR K. pneumoniae sensitive to colistin. The researchers also discovered similar genes that, upon inactivation, can restore susceptibility to beta-lactam antibiotics in MDR E. coli.

“Our discovery shows that resistant superbugs are not invincible. They have an ‘Achilles heel,’ and now we know how to defeat them,” said principal investigator Luca Guardabassi, DVM, PhD.

The new discovery opens the possibility of defeating resistant superbugs by combining antibiotics with “helper drugs” that reverse antibiotic resistance. To date, beta-lactamase inhibitors are the only antibiotic helper drugs used in clinical practice. These agents reverse antibiotic resistance by inhibiting the bacterial enzyme that is responsible for the degradation of beta-lactam antibiotics. The targets identified by the researchers are present in all bacteria and can therefore be used to potentiate antibiotic activity against both  resistant and susceptible strains, according to the investigators.

“In contrast to beta-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,” Guardabassi said.

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. Because of the lack of a valid therapeutic alternative, an older antibiotic, colistin, has become the last resort for managing infections caused by these superbugs, according to the investigators. However, colistin has toxic effects, and its use has selected for mutants that are resistant to all antibiotics.

Source: University of Copenhagen; March 8, 2017.

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