Genome sequence analysis identifies new antimicrobial resistance driver

Antibiotics are a life-saving tool. However, due to their chronic overuse, microbes evolve and develop immunity to them. As a result, once-effective drugs can no longer prevent infections, complicating treatment and increasing mortality.

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

Klebsiella pneumoniae is the third leading cause of bloodstream infections worldwide. It is commonly found on human mucous membranes such as the respiratory system and digestive tract. When given the opportunity to infiltrate, the bacteria can cause pneumonia and serious bloodstream 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 no longer respond 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, conducted with physicians at Dartmouth-Hitchcock Medical Center, we sought to understand the genetic factors that allow Klebsiella pneumoniae to develop resistance to antimicrobials by analyzing the genomic sequences of bacteria from patients diagnosed with bloodstream infections. This work provides insight into how these bacteria develop resistance genes and spread them throughout a population.”

The study is part of a new field called genomic epidemiology, in which scientists track disease-causing bacteria across time and space using whole-genome sequencing to understand how the pathogen evolves and spreads. 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 bloodstream infections at Dartmouth-Hitchcock Medical Center over a five-year period (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. They did. The sample included 64 unique genes encoding resistance to ten classes of antimicrobial drugs. These included strains known to be hypervirulent and multidrug resistant.

The team discovered a crucial way in which K. pneumoniae spreads resistance genes: via plasmids. Plasmids are mobile genetic structures that can carry multiple resistance genes and pass them on to other bacteria. This mechanism facilitates the evolution of a stronger, more resilient bacterial population.

“We discovered that plasmids play a critical role in transmitting genes encoding enzymes that render many antibiotics ineffective,” Andam said. “In particular, we found nearly genetically identical plasmids, carrying genes encoding resistance to multiple antibiotics, in K. pneumoniae recovered from different patients two years apart.”

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

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

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

“Antimicrobial resistance is a global threat as 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 to the RNA Institute at the University at Albany.

“This is a huge problem because the drugs that usually kill these infectious organisms are becoming ineffective. Antimicrobial resistance is thought to be as big a threat to humanity as climate change and world hunger.”

“What Andam’s lab has shown is that genetic elements called plasmids are responsible for converting Klebsiella bacteria into strains that are resistant to multiple antibiotics. These plasmids can move from one pathogen to another, carrying with them genes that cause antibiotic resistance.

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