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.
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 non-resistant infections because they require more tests, need more expensive drugs, and have lengthier stays in hospital.
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.
K.pneumoniae is a common intestinal bacterium 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.
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 Centre for Zoonoses and Tropical 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 defence 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.
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.
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.
