Could new 'helper drugs' restore antibiotic susceptibility in superbugs?

Using state-of-the-art genomics tools, researchers have pinpointed genes that contribute to antibiotic resistance in two global superbugs. They show how such a discovery could lead to "helper drugs" with the potential to restore the susceptibility of resistant bacteria to antibiotics.

The researchers - including some from the University of Copenhagen in Denmark and Ross University School of Veterinary Medicine in St Kitts, West Indies - report their findings in two scientific papers: one published in the journal Scientific Reports, and the other in the journal Antimicrobial Agents and Chemotherapy.

Antimicrobial resistance is a growing threat to global public health, according to the World Health Organization (WHO).

An ever-increasing range of infections caused by bacteria, viruses, parasites, and fungi are becoming resistant to the antimicrobial drugs or antibiotics used to prevent and treat them.

As antibiotics lose effectiveness against resistant "superbugs," patients undergoing surgery and cancer chemotherapy face an added risk of developing potentially severe infections.

The cost of caring for patients infected with superbugs is higher than the cost of caring for patients with nonresistant infections because they require more tests, need more expensive drugs, and have lengthier stays in hospital.

An international review suggested that unless we find new ways to overcome resistant superbugs, the global death toll of antimicrobial resistance will overtake that of cancer and exceed 10 million people per year by 2050.

The Centers for Disease Control and Prevention (CDC) estimate that in the United States, antibiotic resistance is responsible for at least 2,049,442 illnesses and 23,000 deaths every year.

Research focuses on two 'priority 1' pathogens

For their investigation, the researchers focused on two superbugs: one paper describes how they investigated the bacterium Klebsiella pneumoniae, and the other paper describes their work on the bacterium Escherichia coli.

The WHO class both bacteria as "priority 1 pathogens" in their recently published list of global pathogens for which we urgently need new drugs.

K. pneumoniae is a common intestinal bacteria that can give rise to serious, life-threatening infections. It is a major cause of hospital-acquired infections, including pneumonia and bloodstream infections. It can also infect newborns and patients in intensive care units.

Strains of K. pneumoniae that are resistant to last resort treatment with carbapenem antibiotics have now spread to all regions of the world. In some countries, because of resistance, treatment with carbapenem antibiotics is now ineffective in around 50 percent of patients infected with this pathogen.

E. coli is also a common intestinal bacteria - it is often the cause of urinary tract infections (UTIs). There are now many countries where fluoroquinolone antibiotics - drugs that are widely used to treat UTIs - are now ineffective against resistant strains of this pathogen in more than half of patients.

Identifying genes that contribute to antibiotic resistance

The lead investigator of the research on both pathogens was Luca Guardabassi, a professor in veterinary and animal sciences at Copenhagen University and also director of the One Health Center for Zoonoses and Troprical Veterinary Medicine at Ross.

He and his colleagues took a new approach to try and identify genes that might be important to helping the superbugs survive treatment with antibiotics.

Using the latest genomics technology, they assessed the extent to which every single gene in each of the bacteria might contribute to antibiotic resistance.

They identified several genes in multidrug-resistant (MDR) strains of K. pneumoniae that appear to be key to its ability to survive in the presence of colistin - a last-line of defense antibiotic used to treat drug-resistant infections of the pathogen.

To show that their discovery could lead to new drugs (demonstrating "proof of principle"), the team showed that switching off one of the genes, called dedA, completely restored susceptibility of MDR K. pneumoniae to colistin.

The team also conducted similar proof-of-principle tests that showed switching off some of the resistance genes they identified in MDR strains of E. coli restored their susceptibility to beta-lactams - a class of broad-spectrum antibiotics that includes penicillin and carbapenems.

New 'helper drugs' work differently

The authors note that their discovery paves the way to a new type of antibiotic "helper drug" that works differently to beta-lactamase inhibitors - the only type of helper drug already in clinical use. Helper drugs are compounds that when given together with another drug - in this case antibiotics - increase their potency.

Beta-lactamase inhibitors reverse antibiotic resistance by blocking the enzyme in bacteria that breaks down beta-lactam antibiotics. However, the new gene targets that Prof. Guardabassi and colleagues identified are not directly involved with the mechanism of antibiotic resistance itself.

The target genes are present in all bacteria and can therefore be used to make antibiotics more potent in all cases of infection - whether caused by resistant or susceptible strains.

Prof. Guardabassi says: "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 researchers are already investigating how to prevent the selection of resistant mutants. They are testing a combination of colistin with an antifungal drug that is known to disrupt the resistance genes that they identified in MDR K. pneumoniae.

"Our discovery shows that resistant superbugs are not invincible. They have an 'Achilles heel' and now we know how to defeat them."

Prof. Luca Guardabassi

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