Researchers develop molecules for a new class of antibiotics that can overcome drug resistant bacteria

About a decade ago, researchers in the lab of UC Santa Barbara chemistry professor Guillermo Bazan began observing a recurring challenge in their research: Some of the compounds they were making to harvest energy from bacteria, Instead, they were killing microbes. Not good if the plan was to use the metabolism of living bacteria to generate electricity.

“We needed bacteria to survive,” said Alex Moreland, a Cystic Fibrosis Foundation postdoctoral fellow who joined Bazan’s research group as a graduate student in 2014, and is currently at UCSB’s Center for Polymers. and work in organic solids. “When we were developing new molecules for this application, we found that some of them weren’t working because they were killing the bacteria.”

However, rather than dismiss it as a pesky laboratory curiosity, subsequent research by the team turned to the apparent antimicrobial properties of these compounds, known as conjugated oligoelectrolytes (COE). Fast-forward to today, and they now have the foundation for a new class of antibiotics, which not only show promise against a wide array of bacterial infections, but can also avoid the dreaded resistance that our current generation has developed. Presenting the first row of Antibiotics ineffective.

“We realized that the molecular framework that we had been working on for some time, if designed properly, could lead to a new class of antibiotics; something that is rarely seen,” Bazan said. is found and has profound implications for modern medicine,” Bazan said.

Bazan group’s proof-of-concept studies on a wide range of bacterial infections are published in numerous papers. Science Translational Medicinethe Journal of Medicinal ChemistryAnd Chemical Communications.

A global problem

Called a neglected epidemic, antimicrobial resistance (AMR) is a global problem that affects all walks of life. In 2019, an estimated 1.3 million deaths worldwide could be attributed to AMR.

“This data assumes that if the resistant bacteria had been replaced by the same type of non-resistant bacteria, the patients would have survived,” Moreland said. “These are additional deaths that are specifically related to resistance to antibiotics that were effective in previous years.” In many cases, he added, the mortality rate for infections with certain resistant bacteria is three times higher than for non-resistant strains.

Antibiotic resistance develops when bacteria are exposed to antibiotics and develop ways to defeat or bypass the antibiotic. Strategies include: Cell membrane As a barrier, destroying the offending molecule or eliminating it from the cell, or altering the drug’s target to render the antibiotic ineffective. This Resistance mechanisms Inbred bacteria can be transmitted or shared with other bacteria in the environment.

“There were 4.95 million deaths linked to antibiotic resistance in 2019, including 1.3 million deaths directly attributable to AMR, while nearly 10 million people die from cancer each year,” commented Bazan. Bazan commented. “However, the last time we checked there were 27. Clinical trials for new antibiotics and 1,300 for anticancer treatments. It’s worth taking a moment to consider these numbers.”

Broadly effective, yet highly selective

COEs appear to target multiple targets by “remodeling” bacterial membranes, an international team of researchers demonstrated. Science Translational Medicine. Led by Kaixi Zhang, currently a National University of Singapore (NUS) postdoctoral researcher in the Bazan lab, the team deployed their compounds against a particularly difficult-to-treat microbe, Mycobacterium abscessus (Mab), whose Infections are common. Patients with underlying lung diseases, such as cystic fibrosis.

Not only does Mab have an “extraordinarily thick and impermeable cell envelope” that repels antibiotics, it also has the ability to hide inside phagocytes, Immune cells whose function is to envelop and kill microorganisms.

In the case of Mab, these immune cells do not effectively kill the bacteria and can inadvertently make them resistant to antibiotics. Current treatments often fail with combinations of three to four antibiotics for 12 to 18 months—more than half of patients do not recover, yet more than 70% suffer from significant adverse effects. In this study, COE was more effective than the antibiotic controls amikacin and imipenem in eradicating Mab in both in vitro and in vivo experiments.

The researchers attribute this effectiveness to the compound’s targeting of the physical and functional integrity of the bacteria’s cell wall.

“If you destroy the membrane, the cell will burst and of course it will kill the bacteria, but it’s not a selective mechanism,” Zhang said. “However, the membrane has many essential functions that can be inhibited by more subtle membrane targeting. Our hypothesis is that our compounds, by remodeling the membrane, inhibit multiple essential functions simultaneously.” This barrier attack has a multiplier effect on bacteria, making it 10 to 1,000 times more difficult for them to develop resistance than conventional antibiotics, he added.

The unique mechanism of COEs is also of great importance in another aspect of antibiotic resistance or tolerance: biofilm formation, a condition in which a group of microbes form together and form a polymeric substance, which A kind of shield is formed.

I Journal of Medicinal ChemistryLed by UCSB/NUS postdoctoral researcher Jakkarin Limwongyut, the team demonstrated the efficacy of another COE compound against Pseudomonas aeruginosa, a biofilm-forming drug-resistant bacterium identified by the World Health Organization for Disease Control and Prevention. Considered an immediate threat to the centers of is among the pathogens traditionally associated with AMR. It causes a variety of illnesses, from ear infections to life-threatening pneumonia, and is particularly common in hospital settings.

“Some antibiotics cannot penetrate a biofilm, but when bacteria form a biofilm, their metabolism changes because they have less access to nutrients,” Lemongiot said, explaining that the slower metabolism Can make the effects of an antibiotic more tolerable to pathogens. And therefore less effective. “Recalcitrant and recurrent infections, whether UTIs, pneumonia, endocarditis, or diabetic foot ulcer infections, are often associated with biofilms,” he said.

The team demonstrated that their COE compound is capable of killing bacteria in established biofilms while also inhibiting the formation of biofilms. This is a rare one-two punch in the world of antibiotics.

“There are many antibiotics that have anti-biofilm activity, but they’re either not used systemically or they’re used systemically but really shouldn’t be,” Moreland said, among them. Pointing to the high toxicity of some antibiotics, for example, polymyxins are effective against biofilms in a topical form, but are toxic to the kidneys in a systemically administered dose (intravenous injection). Polymyxins accumulate in patients’ kidneys, causing cell and tissue damage and, in severe cases, leading to kidney transplants.

In contrast, the Bazan lab has developed COEs to be highly selective for bacteria. I Chemical Communications, Moreland and team investigated how the structural properties of these molecules could enhance their affinity for bacterial membranes and their antibiotic activity without “detergent-like” effects. In soaps, the antibacterial action relies on the indiscriminate destruction of cell membranes.

“Your skin cells are very good at tolerating soaps and detergents, but other cells in your body, and especially red blood cells, are very sensitive,” he said, which is why that these compounds are only used externally or to decontaminate surfaces and not therapeutically; For the agents COEs, they found, membrane permeability and antibiotic action are not intrinsically linked, suggesting a novel mechanism behind the activity of COEs and, critically, a mechanism that is similar to that in mammals. Can be highly selective for bacterial membranes. Indeed, I molecules Mab The experiment was able to reach inside the phagocytes to kill the bacteria without damaging the mammalian cells.

“We don’t know the exact mechanism yet, but we can definitely show that COEs kill bacteria and not mammalian cells,” Moreland said. “This is not necessarily the case with the original molecules that we initially discovered, but with A lot of chemistryAnd Help with tools like machine learningwe were able to determine the balance between efficacy against which molecular structures. Bacteria and safety to mammals.” In various infection models, mice appear to tolerate COE treatment quite readily.

Look ahead

It’s still early days for Bazan’s research group, now based mostly in Singapore, as they continue to investigate mechanisms of action, find additional new properties and design and improve their molecules. Ideally, COE antibiotics will someday serve as a safe and effective treatment, effective even in the most resistant bacterial infection cases.

Still, the road to clinical trials is long, albeit with interest and support from various institutions and research collaborations around the world, from the Singapore Center for Environmental Life Sciences to the Cystic Fibrosis Foundation and the Walter Reed Army Institute of Research. United States

“So far, so good. The COEs have worked well in the experiments we’ve done to date,” Moreland said, adding that the studies further refined the molecules before advancing them to clinical trials. Required. “Obviously more development is needed but we’re depending on it.”