Oregon State University researchers have developed a new weapon in the battle against antibiotic-resistant germs – a molecule that neutralizes the bugs’ ability to destroy the antibiotic.
Scientists at OSU were part of an international collaboration that demonstrated the molecule’s ability to inhibit expression of an enzyme that makes bacteria resistant to a wide range of penicillins.
The molecule is a PPMO, short for peptide-conjugated phosphorodiamidate morpholino oligomer. The enzyme it combats is known as New Delhi metallo-beta-lactamase, or NDM-1, and it’s accompanied by additional genes that encode resistance to most if not all antibiotics.
“We’re targeting a resistance mechanism that’s shared by a whole bunch of pathogens,” said Bruce Geller, professor of microbiology in OSU’s College of Science and College of Agricultural Sciences, who’s been researching molecular medicine for more than a decade. “It’s the same gene in different types of bacteria, so you only have to have one PPMO that’s effective for all of them, which is different than other PPMOs that are genus specific.”
The Oregon State study showed that in vitro the new PPMO restored the ability of an antibiotic — in this case meropenem, an ultra-broad-spectrum drug of the carbapenem class — to fight three different genera of bacteria that express NDM-1. The research also demonstrated that a combination of the PPMO and meropenem was effective in treating mice infected with a pathogenic strain of E. coli that is NDM-1 positive.
Results of the study, supported by a grant from the National Institutes of Health, were recently published in the Journal of Antimicrobial Chemotherapy.
Geller says the PPMO will likely be ready for testing in humans in about three years.
“We’ve lost the ability to use many of our mainstream antibiotics,” Geller said. “Everything’s resistant to them now. That’s left us to try to develop new drugs to stay one step ahead of the bacteria, but the more we look the more we don’t find anything new. So that’s left us with making modifications to existing antibiotics, but as soon as you make a chemical change, the bugs mutate and now they’re resistant to the new, chemically modified antibiotic.”
That progression, Geller explains, made the carbapenems, the most advanced penicillin-type antibiotic, the last line of defense against bacterial infection.
“The significance of NDM-1 is that it is destroys carbapenems, so doctors have had to pull out an antibiotic, colistin, that hadn’t been used in decades because it’s toxic to the kidneys,” Geller said. “That is literally the last antibiotic that can be used on an NDM-1-expressing organism, and we now have bacteria that are completely resistant to all known antibiotics. But a PPMO can restore susceptibility to antibiotics that have already been approved, so we can get a PPMO approved and then go back and use these antibiotics that had become useless.”
Each year, approximately 700,000 people die from drug-resistant bacterial infections. A study by UCLA life scientists could be a major step toward combating drug-resistant infections. The research, reported in the journal Royal Society Interface, found that combinations of three different antibiotics can often overcome bacteria’s resistance to antibiotics, even when none of the three antibiotics on their own — or even two of the three together — is effective.
In response to drug-resistant “superbugs” that send millions of people to hospitals around the world, scientists are building tiny, “molecular drill bits” that kill bacteria by bursting through their protective cell walls.
They presented some of the latest developments on these drill bits, better known to scientists as antimicrobial peptides (AMPs), at the 247th National Meeting & Exposition of the American Chemical Society (ACS), the world’s largest scientific society.
The meeting, which features more than 10,000 scientific reports across disciplines from energy to medicine, continues here through Thursday.
One of the researchers in the search for new ways to beat pathogenic bacteria is Georges Belfort, Ph.D. He and his team have been searching for a new therapy against the bacteria that cause tuberculosis (TB). It’s a well-known, treatable disease, but resistant strains are cropping up. The World Health Organization estimates that about 170,000 people died from multidrug-resistant TB in 2012.
“If the bacteria build resistance to all current treatments, you’re dead in the water,” said Belfort, who is at Rensselaer Polytechnic Institute.
To avoid this dire scenario, scientists are developing creative ways to battle the disease. In ongoing research, Belfort’s group together with his wife, Marlene Belfort, and her group at the University at Albany are trying to dismantle bacteria from within. They also decided to attack it from the outside.
Studies in Chicago metro-area unveil concerning trends, urban sites most impacted
Triclosan – a synthetic antibacterial widely used in personal care products – is fueling the development of resistant bacteria in streams and rivers. So reports a new paper in the journal Environmental Science and Technology, which is the first to document triclosan resistance in a natural environment.
Invented for surgeons in the 1960s, triclosan slows or stops the growth of bacteria, fungi, and mildew. Currently, around half of liquid soaps contain the chemical, as well as toothpastes, deodorants, cosmetics, liquid cleansers, and detergents. Triclosan enters streams and rivers through domestic wastewater, leaky sewer infrastructure, and sewer overflows, with residues now common throughout the United States.
Emma Rosi-Marshall, one of the paper’s authors and an aquatic ecologist at the Cary Institute of Ecosystem Studies in Millbrook, New York explains: “The bacterial resistance caused by triclosan has real environmental consequences. Not only does it disrupt aquatic life by changing native bacterial communities, but it’s linked to the rise of resistant bacteria that could diminish the usefulness of important antibiotics.”
With colleagues from Loyola University and the Illinois Sustainable Technology Center, Rosi-Marshall explored how bacteria living in stream and river sediments responded to triclosan in both natural and controlled settings. Field studies were conducted at three sites in the Chicago metropolitan region: urban North Shore Channel, suburban West Branch Dupage River, and rural Nippersink Creek.
Urbanization was correlated with a rise in both triclosan concentrations in sediments and the proportion of bottom-dwelling bacteria resistant to triclosan. A woodland creek had the lowest levels of triclosan-resistant bacteria, while a site on the North Shore Channel downstream of 25 combined sewer overflows had the highest levels.
Combined sewers deliver domestic sewage, industrial wastewater, and storm water to a regional treatment plant using a single pipe. Overflows occur when a pipe’s capacity is exceeded, typically due to excessive runoff from high rainfall or snowmelt events. The result: untreated sewage flows directly into rivers and streams.
The research team found that combined sewer overflows that release untreated sewage are a major source of triclosan pollution in Chicago’s North Shore Channel. In addition, their findings support past work that indicates sewage treatment plants can effectively remove triclosan from wastewater.
John Kelly of Loyola University Chicago, the paper’s senior author, comments, “We detected much lower levels of triclosan at a site downstream of a sewage treatment facility as compared to a site downstream of combined sewer overflows. And we demonstrated a strong link between the presence of triclosan in the environment and the development of triclosan resistant bacteria.”
Nearly 800 cities in the United States rely on combined sewer overflows, with the Environmental Protection Agency citing them as a major water pollution concern.
Artificial stream experiments, conducted at Loyola University, confirmed field findings that triclosan exposure triggers an increase in triclosan-resistant bacteria. In addition to the creation of these resistant bacteria, researchers also found a decrease in the diversity of benthic bacteria and a shift in the composition of bacterial communities. Most notable were a 6-fold increase in cyanobacteria and a dramatic die-off of algae.
Rosi-Marshall explains how these shifts could affect aquatic life, “Cyanobacteria are less nutritious than algae and can produce toxins. In triclosan-polluted streams and rivers, changes in microbial communities could negatively affect ecological function and animal communities.”