A chilling commentary of the future of antibiotics

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The health care market is failing to support new antibiotics used to treat some of the world’s most dangerous, drug-resistant “superbugs,” according to a new analysis by University of Pittsburgh School of Medicine infectious disease scientists.

In a study published today in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology, investigators used nationwide prescription data to determine that the current annual U.S. sales of new antibiotics to treat carbapenem-resistant Enterobacteriaceae (CRE), one of the world’s most insidious drug-resistant bacteria, is about $101 million annually — significantly short of the $1 billion believed to be necessary to assure the financial viability of a new antibiotic. Even if new anti-CRE agents were used as widely as possible to treat CRE infections, the projected market size is only $289 million.

“New drugs against CRE address a major, previously unmet medical need and are critical to save lives. If the market can’t support them, then that is a chilling commentary on the future of antibiotic development,” said lead author Cornelius J. Clancy, M.D., associate professor of medicine and director of the mycology program and Extensively Drug Resistant Pathogen Laboratory in Pitt’s Division of Infectious Diseases. “Without antibiotics against increasingly resistant bacteria and fungi, much of modern medicine may become infeasible, including cancer chemotherapies, organ transplantation and high-risk abdominal surgeries.”

CRE infections are estimated to cause 1.5 to 4.5 million hospitalizations worldwide each year. The Centers for Disease Control and Prevention has classified CRE as urgent threat pathogens and calls them the “nightmare bacteria.” The World Health Organization and Infectious Disease Society of America have designated CRE as highest priority pathogens for development of new antibiotics.

Since 2015, five antibiotics against CRE have gained U.S. Food and Drug Administration approval and trials have so far shown three of them to be more effective and less toxic than the previous first-line antibiotics. One of the developers of the new anti-CRE drugs — the biopharmaceutical company Achaogen — declared bankruptcy in April because of its steep losses.

After reporting earlier this year that new CRE antibiotics are being prescribed in only about a quarter of infections that warrant them, Clancy and senior author M. Hong Nguyen, M.D., Pitt professor of medicine and director of UPMC’s Antimicrobial Management Program, investigated the market needed to make antibiotic development sustainable. They found a shortfall in revenue potential, evidenced by the financial difficulties faced by drug companies that created the new anti-CRE drugs.

“The prudent approach when fighting bacteria is to have multiple treatment options in the pipeline so that when resistance is inevitably developed to the current drug, a new antibiotic is waiting in the wings,” said Nguyen. “But we found that market prospects will become even more daunting if more anti-CRE drugs are approved, which is bad news for infectious disease physicians and, more importantly, our patients.”

Clancy and Nguyen propose a combination of “push” and “pull” incentives to encourage sustainable antibiotic development, starting with approval of the bilateral DISARM Act, which currently is under consideration in Congress. DISARM would assure full Centers for Medicare and Medicaid Services reimbursement for use of new antibiotics against resistant infections in hospitalized patients, rather than subsuming antibiotic costs into the discounted bundled payment hospitals receive. This would remove the disincentive hospitals face in using more effective but more expensive new agents rather than cheaper, older agents.

There also needs to be a cultural and behavioral change among hospitals and clinicians to encourage faster adoption and appropriate use of new antibiotics, the researchers said. Infectious disease physicians and pharmacists need to take responsibility for educating the wider clinical community about the importance of quickly updating and following guidelines on the best possible antibiotics to be using for their patients.

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Could an element in green tea help eliminate antibiotic resistant bacteria

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Scientists at the University of Surrey have discovered that a natural antioxidant commonly found in green tea can help eliminate antibiotic resistant bacteria.

The study, published in the Journal of Medical Microbiology, found that epigallocatechin (EGCG) can restore the activity of aztreonam, an antibiotic commonly used to treat infections caused by the bacterial pathogen Pseudomonas aeruginosa.

P. aeruginosa is associated with serious respiratory tract and bloodstream infections and in recent years has become resistant to many major classes of antibiotics. Currently a combination of antibiotics is used to fight P. aeruginosa. However, these infections are becoming increasingly difficult to treat, as resistance to last line antibiotics is being observed.

To assess the synergy of EGCG and aztreonam, researchers conducted in vitro tests to analyse how they interacted with the P. aeruginosa, individually and in combination. The Surrey team found that the combination of aztreonam and EGCG was significantly more effective at reducing P. aeruginosa numbers than either agent alone.

This synergistic activity was also confirmed in vivo using Galleria mellonella (Greater Wax Moth larvae), with survival rates being significantly higher in those treated with the combination than those treated with EGCG or aztreonam alone. Furthermore, minimal to no toxicity was observed in human skin cells and in Galleria mellonella larvae.

Researchers believe that in P. aeruginosa, EGCG may facilitate increased uptake of aztreonam by increasing permeability in the bacteria. Another potential mechanism is EGCG’s interference with a biochemical pathway linked to antibiotic susceptibility.

Lead author Dr Jonathan Betts, Senior Research Fellow in the School of Veterinary Medicine at the University of Surrey, said: “Antimicrobial resistance (AMR) is a serious threat to global public health. Without effective antibiotics, the success of medical treatments will be compromised. We urgently need to develop novel antibiotics in the fight against AMR. Natural products such as EGCG, used in combination with currently licenced antibiotics, may be a way of improving their effectiveness and clinically useful lifespan.”

Professor Roberto La Ragione, Head of the Department of Pathology and Infectious Diseases in the School of Veterinary Medicine at the University of Surrey, said: “The World Health Organisation has listed antibiotic resistant Pseudomonas aeruginosa as a critical threat to human health. We have shown that we can successfully eliminate such threats with the use of natural products, in combination with antibiotics already in use.  Further development of these alternatives to antibiotics may allow them to be used in clinical settings in the future.”

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Helping to solve the antibiotic resistance problem with fungus-farming ants

This image shows leafcutter ants. CREDIT Steve Kett

For the last 60 million years, fungus-growing ants have farmed fungi for food. In their cultivation of those fungi, they’ve successfully relied on bacteria-produced antimicrobial ingredients to protect their crops from other species of parasitic fungi. Now, researchers reporting in the journal Trends in Ecology & Evolution say they are looking to these ants to find new ways to stop or slow the evolution of antibiotic resistance that now presents a major threat to modern medicine.

“Somehow the ant-bacteria alliance seems to have been able to sidestep the problem of antibiotic resistance,” says Massimiliano Marvasi of the Università degli Studi di Firenze, Italy. “This led us to hypothesize that the application of potent cocktails of continually evolving variants of antimicrobial compounds was the most likely model by which to explain this dynamic.”

Marvasi’s team had been studying the fitness of multi-drug resistant pathogens in the environment. While exploring this, first author of the new review Ayush Pathak suggested that they compare what they saw in other environments including clinics to what happens in the fungus gardens of attine ants.

In clinical settings, antimicrobial use leads quickly to the rise of resistant bacterial strains. But the ants weren’t having this same problem. The question was: Why?

The researchers say that the secret to the ants’ success may be explained by the fact that the bacteria they associate with rely on antimicrobials that vary subtly and continually over time in both structure and combination. This element of surprise, enabled by the presence of gene clusters under selective pressure, allows the ant-associated bacteria to produce ever-changing and unpredictable antimicrobials. As a result, it’s much tougher for the parasitic fungi to become resistant, even over the course of millions of years.

The ants’ example suggests that mixing and administering continually varying cocktails of slight structural variants of known antibiotics might hold promise as a means to address antimicrobial resistance in the clinic, the researchers say. Along with the continued development of new molecules and classes of antibiotics, they suggest this strategy should now be assessed in the lab and ultimately in the clinic.

“I think the development of effective strategies for mixing subtle antibiotic variants could give a new life to old antibiotics,” Marvasi says.

The researchers say the next step is to investigate the effects of selection pressure upon the bacterial gene clusters that produce antibiotic variants. “A better understanding of this relationship and its coevolutionary processes at the genetic level will complement development of new strategies for combating the rise of resistance as well as potentially giving rise to novel antibiotic compounds,” Pathak says.

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A new way to kill pathogens resistant to antibiotics

A solution of the extracellular heme acquisition system protein A (HasA) with gallium phthalocyanine (Left) and the results of sterilization of Pseudomonas aeruginosa and Escherichia coli treated with HasA-bound gallium phthalocyanine by irradiation with near-infrared light (Right). Credit: Osami Shoji

A new Trojan horse approach could lead to treatments for some antibiotic-resistant bacteria.

A deadly, antibiotic-resistant bacterium can be sterilized by hijacking its haem-acquisition system, which is essential for its survival. The new strategy, developed by Nagoya University researchers and colleagues in Japan, was published in the journal ACS Chemical Biology.

Pseudomonas aeruginosa is a dangerous bacterium that causes infections in hospital settings and in people with weakened immune systems. It can cause blood infections and pneumonia, while severe infections can be deadly. Highly resistant to antibiotic treatment, P. aeruginosa is one of the most critical pathogens urgently requiring alternative treatment strategies, according to the World Health Organization.

This bacterium is one of many that have evolved a system that allows them to acquire difficult-to-access iron from the human body. Iron is essential for bacterial growth and survival, but in humans, most of it is held up within the ‘haem’ complex of haemoglobin. To get hold of it, P. aeruginosa and other bacteria secrete a protein, called HasA, which latches onto haem in the blood. This complex is recognized by a membrane receptor on the bacterium called HasR, permitting haem entry into the bacterial cell, while HasA is recycled to pick up more haem.

Bioinorganic chemist Osami Shoji of Nagoya University and collaborators have found a way to hijack this ‘haem acquisition system’ for drug delivery. They developed a powder formed of HasA and the pigment gallium phthalocyanine (GaPc), which, when applied to a culture of P. aeruginosa, was consumed by the bacteria.

“When the pigment is exposed to near-infrared light, harmful reactive oxygen species are generated inside the bacterial cells,” explains Shoji. When tested, over 99.99% of the bacteria were killed following treatment with one micromolar of HasA with GaPc and ten minutes of irradiation.

The strategy also worked on other bacteria with the HasR receptor on their membranes, but not on ones without it.

The haem acquisition system is so essential to these bacteria’s survival that it is not expected to change, making it unlikely the bacteria will develop resistance to this drug strategy, the researchers believe.

“Our findings support the use of artificial haem proteins as a Trojan horse to selectively deliver antimicrobials to target bacteria, enabling their specific and effective sterilization, irrespective of antibiotic resistance,” the team reports in their study.

The researchers next aim to test their strategy for treating infections, and are working on modifying their approach for sterilizing other pathogens that possess a similar haem acquisition system.

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Overcoming antibiotic resistance in Staph infections has a potent new weapon

Pseudomonas aeruginosa-produced rhamnolipids target the plasma membrane of Staphylococcus aureus (red) to increase permeability to aminoglycoside antibiotics.

UNC School of Medicine researchers led by Brian Conlon, PhD, discover how molecules called rhamnolipids could make common aminoglycoside antibiotics effective against the toughest Staph infections.

Staphylococcus aureus bacteria are a major cause of serious infections that often persist despite antibiotic treatment, but scientists at the UNC School of Medicine have now discovered a way to make these bacteria much more susceptible to some common antibiotics.

The scientists, in a study published in Cell Chemical Biology, found that adding molecules called rhamnolipids can make aminoglycoside antibiotics, such as tobramycin, hundreds of times more potent against S. aureus – including the strains that are otherwise very hard to kill. The rhamnolipids effectively loosen up the outer membranes of S. aureus cells so that aminoglycoside molecules can get into them more easily.

“There’s a great need for new ways to kill bacteria that tolerate or resist standard antibiotics, and to that end we found that altering membrane permeability to induce aminoglycoside uptake is an extremely effective strategy against S. aureus,” said study senior author Brian Conlon, PhD, an assistant professor in the department of microbiology and immunology at the UNC School of Medicine.

The U.S. Centers for Disease Control has estimated that in 2017 there were more than 119,000 cases of serious bloodstream Staph infections in the United States, of which more than 20,000 were fatal.

Standard treatments for many strains of the S. aureus do not kill the bacteria, either because the bacteria have genetically acquired specific antibiotic resistance or because they grow in the body in a way that makes them inherently less vulnerable. For example, S. aureus can adapt its metabolism to survive in low-oxygen zones in abscesses or in the mucus-filled lungs of people with cystic fibrosis. In these environments, the bacterial outer wall or membrane becomes relatively impermeable to aminoglycosides, such as tobramycin.

Conlon and colleagues, including first author Lauren Radlinski, a PhD candidate in the Conlon laboratory, found in a 2017 study that rhamnolipids greatly enhance tobramycin’s potency against standard test strains of S. aureus. Rhamnolipids are small molecules produced by another bacterial species, Pseudomonas aeruginosa, and are thought to be one of P. aeruginosa’s natural weapons against other bacteria in the wild. At high doses they make holes in rival bacteria’s cell membranes. The UNC researchers found that rhamnolipids greatly boost the uptake of tobramycin molecules, even at low doses where they have no independent anti-bacterial effect.

In the new study, Conlon, Radlinski and colleagues tested rhamnolipid-tobramycin combinations against S. aureus populations that are particularly hard to kill in ordinary clinical practice. The researchers found that rhamnolipids boost tobramycin’s potency against:

• S. aureus growing in low-oxygen niches;

• MRSA (methicillin-resistant S. aureus), which are a family of dangerous S. aureus variants with genetically acquired treatment resistance;

• tobramycin-resistant S. aureus strains isolated from cystic fibrosis patients;

• and “persister” forms of S. aureus that normally have reduced susceptibility to antibiotics because they grow so slowly.

Radlinski said, “Tobramycin doses that normally would have little or no effect on these S. aureus populations quickly killed them when combined with rhamnolipids.”

Conlon, Radlinski, and colleagues determined that rhamnolipids even at low doses alter the S. aureusmembrane in a way that makes it much more permeable to aminoglycosides. Each antibiotic in this family that they tested – including tobramycin, gentamicin, amikacin, neomycin, and kanamycin – had its potency enhanced. The experiments showed, moreover, that this potency-boosting strategy is effective not just against S. aureus but several other bacterial species, including Clostridioides difficile (C-diff), which is a major cause of serious, often-fatal diarrheal illness among the elderly and patients in hospitals.

Rhamnolipids come in many variants, and the scientists now hope to determine if there is an optimal variant that works powerfully against other bacteria while having little or no toxic effect on human cells. The team also plans to study other microbe-vs.-microbe weapons to find new ways to enhance the potency of existing antibiotics.

“There’s a huge number of bacterial interspecies interactions that could be influencing how well our antibiotics work,” Radlinski said. “We aim to find them with the ultimate goal of improving the efficacy of current therapeutics and slowing the rise of antibiotic resistance.”

Learn more: Scientists Find Powerful Potential Weapon to Overcome Antibiotic Resistance

 

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