Significant Advance Reported in the Battle against Multidrug-Resistant Bacteria

Researchers from the Novo Nordisk Foundation Center for Biosustainability at the Technical University of Denmark report that antibiotic-resistant Pseudomonas infections in cystic fibrosis (CF) patients show predictable sensitivities to other classes of antibiotics. The scientists believe that this finding could lead to new ways of optimizing treatments for chronic infections.

“Our discovery of widespread antibiotic sensitivities in the multidrug-resistant pathogen Pseudomonas aeruginosa opens up the opportunity to limit the development of antibiotic resistance and perhaps even revert it. This could be important for the treatment of several chronic infections, including the life-long lung infections of patients with cystic fibrosis,” says Morten Sommer, Ph.D., professor and scientific director at the Novo Nordisk Foundation Center for Biosustainability,

The researchers found a number of antibiotic vulnerabilities of multidrug-resistant pathogens were preserved across clinical isolates isolated over decades at the CF clinic at Rigshospitalet in Copenhagen. In a study (“Drug-Driven Phenotypic Convergence Supports Rational Treatment Strategies of Chronic Infections”) published in Cell, the team noted that it then became possible to identify the underlying mutations that caused the sensitivity.

“Chronic Pseudomonas aeruginosa infections evade antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P. aeruginosa toward clinically relevant antibiotics leads to phenotypic convergence toward distinct states. These states are associated with collateral sensitivity toward several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients,” write the investigators.

“In-depth investigation of chronic P. aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.”

“Targeting vulnerabilities of phenotypic states related to specific mutations could potentially have a huge impact because it makes it possible to make a more personalized treatment strategy for each patient,” says Lejla Imamovic, Ph.D., senior researcher at the Novo Nordisk Foundation Center for Biosustainability. “Results indicate that for some antibiotics, exposure and subsequent resistance evolution leads to convergence toward specific phenotypes states. Thus, collateral sensitivity may be particularly useful for optimizing treatments of chronic infections since their nature and severity warrants and requires tailored treatment strategies.”

The current thinking on resistance evolution suggests that pathogens causing chronic infections become increasingly resistant in response to antibiotic treatment, according to Dr. Imamovic. Yet, the findings of widespread collateral sensitivity interactions among clinically applied drugs anticipate that the resistance profiles of chronic infecting bacteria would fluctuate over time in response to different drug exposures, explains Dr. Sommer.

“Our research supports the notion that treatment of chronically infected patients could be significantly improved based on specific diagnostic markers that are associated with a collateral sensitivity to specific drugs,” he says.

Some of the team’s findings relate to drugs that are already used clinically and it is possible that benefits can be gained simply by making slight changes to the empirical treatment prescribed by physicians now, adds Dr. Sommer.

But he emphasizes that “larger controlled clinical trials will also be important in order to fully exploit these findings in the clinic.”