The ‘discovery void’ refers to the period from 1987 to today, when lipopeptides, the last class of antibiotics to be successfully introduced as a treatment, were adapted. It is extremely difficult to develop an antibiotic drug, often taking ten years or more, and efforts to screen libraries of small molecules to find new drug candidates have failed. Pharma companies aren’t especially interested in funding research into new antibiotics due to the expense and risk, and instead have gravitated towards developing drugs for chronic health conditions, which are a growing problem in aging populations.
For modern medicine, this lack of new antibiotics is a big problem. Overuse of antibiotics in agriculture and animal husbandry, over-prescribing and poor medication adherence is consistently leading to a phenomenon known as antimicrobial resistance (AMR), where microorganisms mutate and develop resistance to antimicrobials due to repeat exposure. AMR has been listed as one of the most significant threats to humanity by the World Health Organization (WHO), and threatens the effective prevention and treatment of infections caused by bacteria, parasites, viruses and fungi.
The Covid-19 crisis may be caused by a novel coronavirus, but it’s given us a sobering picture of a world where just one highly infectious disease has no treatment available. If this were to become the case for the majority of communicable pathogens, as each one gradually mutates and becomes resistant to the medications we currently use to treat it, it could spell disaster for the future of humankind.
However, Australian biotech firm Recce Pharmaceuticals may have a solution. Its lead compound, RECCE 327, is a synthetic broad-spectrum antibiotic that the company hopes can eliminate the problem of AMR for good.
Recce executive director of regulatory affairs Michele Dilizia says: “We’re offering a completely different synthetic class of antibiotics. We’re not limited to what nature offers. We get to choose our chemicals, design our molecule and importantly create a unique and universal mechanism of action.”
Recce: a ‘master key’ to unlock all bacterial cells
RECCE 327 has, thus far, destroyed every bacterium it’s been tested against, including superbugs, and no bacteria has been able to mutate to overcome it. It’s been trialled against sepsis and pre-septic kidney and urinary tract infections (UTIs), wound infection, gastritis and gonorrhoea, as well as a number of viral respiratory infections. The drug is heading towards first-in-human safety trials for the intravenous treatment of blood infections at the end of 2020, as well as a Phase I safety and efficacy trial into the use of the compound as a topical application for infected wounds.
“The inherent weakness of antibiotics based on natural sources is that they all kill bacteria on what I call a ‘lock and key’ mechanism of action,” says Dilizia. “If the antibiotic is the key, the bacterium is the lock. It’s got to be that precise fit. It’ll work for a while until the bacteria mutate and change the lock, and that’s happening with ever more frequency.”
When RECCE 327 enters the bloodstream, it uses a hydrophobic reaction to bind to the outer membrane of an infectious bacterium. This weakens the cell wall and causes internal pressure inside the cell to build. The pathogen then bursts, after which the body’s own immune system can come in to clear away the debris. Normal non-bacterial cells, like red blood cells, remain intact as they do not contain the same kind of high internal pressures as certain pathogens.
Because this mode of action is universal, it’s almost like having a master key to ‘unlock’ all bacterial cells.
The drug that keeps on killing
“I joined the company eight years ago as a qualified medical scientist and worked on the first in vitro testing of the antibiotics,” says Dilizia. “We were testing to see that not only would our antibiotic kill bacteria, but importantly it kept on killing them with repeated exposure.”
And keep on killing with repeated exposure RECCE 327 has. Thus far, testing has shown no signs that the drug’s potency lessens with repeated use, and its unique method of action means it can overcome microbial mutations.
“The personal antibiotics that we have are becoming weaker and less effective in combating ever-mutating and more powerful superbugs,” says Dilizia.
“It is very worrying because if we don’t have really good antibiotics to help fight infection then we can say goodbye to all the very good things in modern medicine that we take for granted. We wouldn’t be able to support effective chemotherapy or immunotherapy or all of the wonderful advances in surgeries like hip and knee replacements, brain surgery and caesarean section. All those things depend completely on effective antibiotics.”
The compound has now been awarded qualified infectious disease product (QDIP) status by the US Food and Drug Administration (FDA), giving it fast-track designation along with ten years of post-approval market exclusivity in the US.
Recce is also permitted to supply RECCE 327 to Australian medical practitioners for seriously ill patients for whom death is reasonably likely to occur within a matter of months or in the absence of early treatment, under the Australian Therapeutic Goods Administration (TGA) Special Access Scheme Category A.
Recce takes on Covid-19
The Covid-19 crisis has had a significant impact on Recce’s operations, something which is perhaps to be expected of an infectious disease in the middle of a pandemic.
While the company hasn’t yet been able to access samples of the novel coronavirus, it has been able to turn its attention to influenza A, one of the three variants of the flu. While influenza A isn’t from the same family of viruses as Covid-19, the particles of both diseases share a common RNA genome. They are also both envelope viruses, viral pathogens with protective layers that shelter their genetic material when travelling between host cells. Using an industry recognised mouse model, Recce decided to test its formula out.
“I don’t hesitate to say that the results for Recce were dramatic,” says Dilizia. “We not only outperformed the lead candidate antiviral to combat flu, but our viral levels in the lungs of the mice became so low they were below the level of quantitation at which the laboratory was able to count them.”
The company’s success in treating influenza A in the mouse model has led to hope that, due to their structural similarities, RECCE 327 could one day be a candidate for treating Covid-19 too.
Overcoming antibiotic allergies
Another issue with current antibiotics, alongside AMR, is the fairly common problem of antibiotic allergy. Around one in 15 people are thought to be allergic to at least one antibiotic, particularly penicillin and cephalosporins. While most people with antibiotic allergies will only experience mild symptoms like skin irritation, in others this can be more serious, even triggering anaphylaxis.
Recce’s formula, however, doesn’t appear to have triggered any allergic reactions in participants of some early non-clinical research.
Dilizia says: “We’ve done extensive non-clinical safety and toxicity studies and not come across allergy to our compound even at very high doses via intravenous administration or for topical applications of the treatment to burns and wounds. We’ve also done sensitivity tests placing a very high concentration of our compound on human volunteers’ skin, and the only allergy we got was from the sticking plaster we had to place on top.”
A drug that has killed every pathogen it has come into contact with, both bacterial and viral, which will keep on killing if the pathogen mutates and to which nobody is allergic almost sounds too good to be true.
It’s worth acknowledging that, while the drug has been tested against several pathogens, it hasn’t been tested against them all and there’s every chance Recce will eventually find a bacterium that, for whatever reason, RECCE 327 cannot kill. But if the drug can prove itself in human trials, this singular compound could completely change the face of healthcare as we know it, wiping out the looming threat of AMR for serious infections like sepsis. For now, it’s a waiting game to see if the drug can overcome this crucial hurdle.
Dilizia says: “We’ve had no new class of antibiotics for some 30 years, and our current antibiotics are all based on natural, specific mechanisms of action that are failing us. They’re failing us now and it’s going to get worse. We’re offering a patented suite of synthetic polymer antibiotics that offer a real, innovative solution to the antibiotic health crisis.”