Discovered new gene so diabolical and robust that it resists one of the world’s few last-resort antibiotics


While sifting through the bacterial genome of salmonella, Cornell food scientists discovered mcr-9, a new, stealthy jumping gene so diabolical and robust that it resists one of the world’s few last-resort antibiotics.

Doctors deploy the antibiotic colistin when all other infection-fighting options are exhausted.

But resistance to colistin has emerged around the globe, threatening its efficacy.

“This last-resort antibiotic has been designated a highest-priority antibiotic by the United Nations’ World Health Organization, and the mcr-9 gene causes bacteria to resist it,” said Martin Wiedmann, Cornell’s Gellert Family Professor in Food Safety and senior author on the study published May 7 in the journal Mbio.

“In treatments, if colistin does not work, it literally could mean death for patients.

If colistin resistance spreads, a lot of people will die.”

Co-lead author Laura Carroll, a computational biologist and Cornell doctoral candidate, found mcr-9 in the genome of a strain of foodborne pathogen salmonella.

Because the DNA sequence of the mcr-9 gene was similar to other genes that could cause bacteria to resist colistin, she suspected that the salmonella strain which carried mcr-9 was colistin-resistant.

To her surprise, the salmonella strain failed to show colistin resistance.

Colistin, also known as polymyxin E, is an antibiotic produced by certain strains of the bacteria Paenibacillus polymyxa.

Colistin is a mixture of the cyclic polypeptides colistin A and B and belongs to the class of polypeptide antibiotics known as polymyxins.

Colistin is effective against most Gram-negative bacilli.

Colistin is a decades-old drug that fell out of favor in human medicine due to its kidney toxicity.

It remains one of the last-resort antibiotics for multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter.

NDM-1 metallo-β-lactamase multidrug-resistant Enterobacteriaceae have also shown susceptibility to colistin.

Resistance to colistin in human pathogens is rare.

The first colistin-resistance gene in a plasmid which can be transferred between bacterial strains was found in 2011 in China and became publicly known in November 2015.

The presence of this plasmid-borne mcr-1 gene was confirmed starting December 2015 in South-East Asia, several European countries and the United States.

Colistin was one of the first antibiotics with significant activity against Gram-negative bacteria, notably Pseudomonas aeruginosa.

It exhibits rapid, concentration-dependent bactericidal activity [24]. CMS was largely replaced by aminoglycosides in the 1970s because of concern about nephrotoxicity and neurotoxicity [58].

In the last 10 – 15 years, however, CMS/colistin has been a limited option and used as ‘salvage’ therapy for infections caused by multidrug-resistant (MDR) Gram-negative bacteria, in particular P. aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae [58]. The lack of alternative antibiotics has been exacerbated by the dry antimicrobial-drug development pipeline [9].

Having entered clinical use in 1959, CMS/colistin was never subjected to drug development procedures that are now mandated by international drug regulatory agencies such as the Food and Drug Administration.

As a result, there is a dearth of pharmacological information informing rational use, which aims to maximize antibacterial activity while minimizing toxicity and development of resistance [58].

There are no scientifically-based dosage regimens for various categories of patients, in particular people with cystic fibrosis (CF) and subsets of critically-ill patients (e.g. with differing levels of renal function including those on renal replacement therapy).

Even though rates of colistin resistance have been relatively low, probably because of its infrequent use, there have recently been several outbreaks of infections caused by colistin-resistant bacteria [1013].

Since no novel antibiotics with activity against Gram-negative bacteria will be available within the next 9 – 11 years [14], there is an urgent need to optimize use of CMS/colistin. Background information on colistin is summarized in recent extensive reviews [58]. 

The resurgence in the use of CMS/colistin began in the late 1980s and early 1990s, when it was administered intravenously and/or by inhalation to manage infections or colonization with P. aeruginosa in pediatric and adult CF.

In the last decade it has been used to treat of a range of infections (e.g. ventilator-associated pneumonia (VAP), bacteremia) caused by MDR Gram-negative bacteria, in particular P. aeruginosa, A. baumannii and K. pneumoniae, in critically-ill adult patients; most typically it is administered intravenously.

Although generally considered to be efficacious and safe in this setting [68] there is a paucity of randomized controlled trials, many studies are retrospective in nature and other antibiotics are often used in combination (e.g. [6846]).

In addition, small sample sizes and resultant lack of power substantially compromise the usefulness of many studies; for example, a recent prospective cohort study in adult critically-ill patients intended to compare high-dose ampicillin/sulbactam versus CMS intravenous monotherapy for treatment of MDR A. baumannii VAP had a power of 6% [47].

Nephrotoxicity and neurotoxicity are the most common adverse effects of intravenous administration of CMS. Neurotoxicity is rare [68226162]. Nephrotoxicity is more common and is of most concern to prescribing clinicians.

A recent retrospective cohort study [22] comparing the safety and efficacy of CMS/colistin and tobramycin for treatment of MDR A. baumannii infections in ICU patients found that the risks of nephrotoxicity were similar.

Knowing that the mcr-9 gene could jump to other bacteria or organisms, her colleague, senior research associate Ahmed Gaballa, a microbiologist and co-lead author, inserted the gene into a nonpathogenic strain of the bacterium E. coli.

The mcr-9 gene’s protein structure graphic depicts the differing protein chains (solid color ribbons) and the protein surface (mesh) surrounding it. Credit: Ahmed Gaballa, Cornell University

Gaballa was able to “turn on” mcr-9, making the E. coli strain resistant to colistin. That showed Carroll was initially correct.

“When we originally tested the salmonella isolate and found that it wasn’t resistant to colistin, we were perplexed,” Carroll said.

“But when Ahmed cloned it into an E. coli host, he was able to find that the gene could confer resistance to colistin.”

Mcr-9 is the latest in this new series of “mobilized colistin-resistance” genes – originally discovered in 2015.

The National Center for Biotechnology Information, part of the National Institutes of Health, has added details about this new gene to its database.

Medical professionals and others can now use this information to identify mcr-9 in bacteria isolated from food products and people.

Details about mcr-9 in national and international databases enable scientists to develop better prevention and treatment, explained Wiedmann.

“This improves our ability to get an early warning,” he said.

Bacteria isolated from food products can now be tested for mcr-9, and patients can be screened for colistin-resistant bacteria which possess mcr-9.

“If you go to a hospital and this gene is floating around, that can be trouble.

The gene is moveable. It jumps,” Wiedmann said.

“In a hospital setting, being able to screen a patient for resistance allows doctors and nurses to isolate the patient and maintain biosecurity.”

Wiedmann pointed out that while his lab is dedicated to food safety, the collaboration of scientists from different fields made the discovery possible.

“In this age of complicated problems, we need the computational bioinformatics approach to find solutions,” he said.

“Standard biological research and standard tests would not necessarily have found this gene.”

Carroll added: “It takes a village of a computational biologist, a microbiologist and a molecular biologist to make this sort of scientific discovery happen.”

More information: Laura M. Carroll et al, Identification of Novel Mobilized Colistin Resistance Gene mcr-9 in a Multidrug-Resistant, Colistin-Susceptible Salmonella enterica Serotype Typhimurium Isolate, mBio(2019). DOI: 10.1128/mBio.00853-19
Journal information: mBio
Provided by Cornell University


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