Genome sequence analysis identifies new driver of antimicrobial resistance

Antibiotics are a lifesaving tool. Yet, due to their chronic overuse, microbes are evolving and developing immunity against them. As a result, once-effective medications can no longer stave off infections, complicating treatment and increasing mortality.

A University at Albany study recently published in the journal Nature Communications identified a new genetic mechanism that allows antimicrobial resistance to spread among lethal bacteria.

The bacterium Klebsiella pneumoniae is the third leading cause of blood infections globally. Commonly found on human mucosal surfaces like the respiratory system and gastrointestinal tract, when given an opportunity to invade, the bacteria can cause pneumonia and serious blood and urinary tract infections. These infections can trigger a powerful immune response that can lead to organ failure and death.

“We know that many medically important bacteria are no longer responding to antibiotics, and some are resistant to multiple drugs,” said co-author Cheryl Andam, associate professor in the Department of Biological Sciences and the RNA Institute.

“In this study, with physicians at the Dartmouth-Hitchcock Medical Center, we sought to understand the genetic factors that enable Klebsiella pneumoniae to develop antimicrobial resistance by analyzing the genome sequences of the bacteria from patients diagnosed with bloodstream infections. This work gives a window into how these bacteria develop resistance genes and spread them through a population.”

The study represents an emerging field called genomic epidemiology, wherein scientists track disease-causing bacteria across time and space using whole genome sequencing to understand how the pathogen is evolving and spreading. This requires identifying all the genes and genetic variants carried by individual bacterial strains within a population.

The researchers analyzed the genetic sequences of 136 K. pneumoniae isolates collected from adult and pediatric patients with blood infections at Dartmouth-Hitchcock Medical Center over a five-year span (2017–2022). They identified 94 distinct genetic sequences, indicating a high level of genetic diversity within the sampled K. pneumoniae population.

They also tested the genome sequences against 20 different antibiotics to determine whether the population included strains known to be resistant. It did. The sample included 64 unique genes encoding resistance to ten antimicrobial drug classes. Among these were strains known to be hypervirulent and multidrug-resistant.

Critically, the team discovered how K. pneumoniae spread resistance genes: via plasmids. Plasmids are mobile genetic structures that can carry multiple resistance genes and spread them to other bacteria. This mechanism facilitates the evolution of a stronger and more resilient bacterial population.

“We found that plasmids are instrumental in the transmission of genes encoding enzymes that render many antibiotics ineffective,” said Andam. “Most notably, we found nearly genetically identical plasmids, carrying genes encoding resistance to multiple antibiotics, in K. pneumoniae recovered from different patients separated by two years.

“This means that these plasmids can persist for a long time and remain effective in disseminating and causing the emergence of multidrug resistant strains, which are very difficult to treat.”

This new understanding will inform strategies for public health interventions aimed at controlling the spread of high-risk bacterial clones.

“Continued surveillance and further genomic epidemiological studies in health care settings will deepen our understanding of plasmid-facilitated antimicrobial resistance and how this mechanism shapes health risks for vulnerable patients and the wider community,” said Andam.

“Antimicrobial resistance is a global threat because microbial diseases caused by bacteria, viruses, parasites and fungi become unresponsive to drug treatment and can cause life-threatening infections,” said Distinguished Professor Marlene Belfort, senior advisor of the RNA Institute at UAlbany.

“That’s a tremendous problem because medicines that ordinarily kill these infectious organisms are becoming ineffective. It’s thought that antimicrobial resistance is an equivalent threat to humankind as climate change and world hunger.

“What the Andam lab has shown is that genetic elements called plasmids are what cause Klebsiella bacteria to convert to strains that are resistant to several antibiotics. These plasmids can move from one pathogenic microbe to another, carrying with them genes that cause antibiotic resistance.

“Understanding the mechanisms by which antibiotic resistance spreads among K. pneumoniae is a critical step towards understanding the broader problem of antimicrobial resistance and developing treatments against dangerous resistant strains.”