Developing Synthetic Antibiotics Against Drug-Resistant Pathogens

The World Health Organization classes antimicrobial resistance as one of the greatest global health threats. A historic lack of innovation and investment in the development of novel antibiotics coupled with the ever-changing, dynamic nature of infectious disease, has enabled the emergence and spread of drug-resistant pathogens. To address this issue, scientists are working to develop new strategies to prevent and manage antimicrobial resistance globally.

Technology Networks spoke with James Graham, Executive Director at Recce Pharmaceuticals, to learn more about how synthetic antibiotics differ from those derived from natural sources. He also discusses how the company has developed a novel class of synthetic antibiotics and elaborates on their mechanism of action.

Laura Lansdowne (LL): Could you comment on the urgent global health threat that has been caused by the emergence of drug-resistant superbugs?

James Graham (JG): Multidrug-resistant bacteria, or superbugs, are on the rise and have outpaced the development of effective antibiotics, threatening our ability to treat common infections and support modern medicine as we know it.

Antibiotics, used to prevent and treat bacterial infections, are becoming increasingly less effective due to antibiotic resistance. Antibiotic resistance occurs when bacteria no longer respond to the drugs designed to kill them but instead continue to grow. This is hastened by decades of overuse and misuse of antibiotics.

Successful surgeries, cancer chemotherapy treatment and low maternal and neonatal mortality all depend on our ability to successfully treat infections. Each year, multidrug-resistant bacterial infections cause hundreds of thousands of deaths worldwide and this number is projected to reach millions over the next three decades.

As bacteria continue to develop resistance to most, if not all, currently approved antibiotics, the need for new antibiotics has never been greater, and the pipeline has never been drier. New types of resistant mechanisms and multidrug-resistant bacteria continue to emerge and spread globally.

LL: Why have no new human antibiotics entered the market since 1987? What are some of the key challenges encountered when developing novel antibiotics?

JG: There is a historic lack of innovation in new antibiotic drug development to address the growing need against drug-resistant superbugs. Almost every antibiotic on the market is based on scientific discoveries from over 30 years ago, and there has not been a new class of antibiotics since.

The global antibiotic pipeline remains deficient as most drugs advancing through the clinic are predominantly derivatives of well-established antibiotic classes and do not include any new class of molecules or new mechanisms of action. The consequences are recognized globally, with bacterial infections becoming more aggressive and harder to treat.

While it is challenging to develop an antibiotic drug, it is also costly and may take ten years or more. Antibiotics can develop resistance fast, which prevents usability, bringing financial hurdles. Additionally, novel antibiotics must be used prudently to avoid resistance development. The loss of expertise and dedicated personnel in the antibiotic field is a result of the technical adversity when developing an antibiotic drug.

Especially challenging, are a group of deadly bacteria, identified by the World Health Organization (WHO), as the ESKAPE pathogens, which are: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter. Approximately 700,000 people die every year from antibiotic-resistant infections globally – many of these are from the ESKAPE pathogens. Due to their rate of mutation, they pose a significant risk to all patients and a heightened threat to those developing antibiotic resistance.

LL: What is the difference between synthetic antibiotics and natural antibiotics? How are synthetics antibiotics designed?

JG: Conventional antibiotics are derived from natural sources, typically by certain fungi or soil bacteria, and therefore rely on timely fermentation processes that require large-scale bacterial culture and then several subsequent purification stages. They are not designed to avoid resistance. In contrast, synthetic antibiotics begin with the end in mind. They are wholly synthesized in a lab, designed by what is required from it.

RECCE® antibiotics are based on a patented polymeric structure and have shown no tendency for the emergence of resistance, even after repeated use, something that commercial antibiotics fail to do.

Additionally, in comparison to the large-scale and timely process to create natural antibiotics, Recce’s synthetic antibiotics is a considerably efficient process and give rise to a 99.9% product yield in several hours. Furthermore, it requires no specialized or expensive waste removal and presents no risk of environmental contamination.

LL: Can you tell us more about the class of synthetic antibiotics you have developed? How does its mode of action differ compared to other antibiotics?

JG: RECCE® 327 represents a new class of synthetic antibiotics with rapid, potent, and broad-spectrum activity against serious and potentially life-threatening multidrug-resistant pathogens. Once Recce’s antibiotics enter the bloodstream, they are attracted to the plasma membranes of bacteria via a hydrophobic interaction. They bind to plasma membrane proteins, subsequently weakening the bacterial cell wall. Due to the unique high metabolic pressure in bacteria, the cell walls collapse or burst (cell lysis), leading to bacterial cell death. Importantly, non-bacterial (eukaryotic) cells remain intact since they do not contain high enough internal pressures to result in cell lysis.

This new class of antibiotics are bactericidal, which means they work by killing the bacteria rather than by inhibiting their growth. Designed to address the global health threat of antibiotic-resistant superbugs, RECCE 327 shows efficacy, even with repeated use.

Traditional antibiotics operate by a “lock and key” mechanism of action. When a bacterium mutates/evolves, that mechanism of traditional antibiotics no longer functions because the lock has changed. The new class of compounds synthesized by Recce are polymeric molecules designed to overcome these limitations. Rather than inhibiting a specific bacterial protein or process, RECCE 327 can overcome potential bacterial mutations through its universal mechanism of action.

RECCE 327 has been awarded a Qualified Infectious Disease Product (QIDP) for sepsis by the US Food and Drug Administration (FDA), labeling it for fast track designation plus 10 years of market exclusivity post approval. This designation fast tracks RECCE 327 through the regulatory review process, so it is available to treat patients with serious or life-threatening bacterial infections sooner.

RECCE antibiotics are easily formulated for topical, nasal, oral, or inhaled use. This versatility will be beneficial when developing antibiotics for indications other than sepsis. In using RECCE 327 as the standard of care, it may also broadly reduce drug resistance against traditional antibiotics. By introducing RECCE 327 as a new treatment option that can reduce the use of traditional antibiotics, it could lower the selective pressure on bacteria that leads to the development of resistance.

LL: What types of bacteria has your new class of synthetic antibiotics demonstrated capability against?

JG: RECCE 327 has demonstrated high potency against a range of Gram-positive and Gram-negative bacterial pathogens.

In Recce’s methicillin-resistant Staphylococcus aureus (MRSA superbug) study, rats with topical burns treated with RECCE 327 demonstrated compelling in vivo antibacterial activity. The results showed that RECCE 327 was effective in reducing bacterial load within a wound and showed enhanced wound contraction compared to the best in class – Soframycin® (framycetin sulfate). RECCE 327 showed repeated efficacy at different dosing levels on topical skin conditions even at low doses.

Another recent study in mice showed RECCE 327 demonstrating significant in vivo antibacterial activity against Neisseria gonorrhoeae, a species of Gram-negative bacteria the second most common sexually transmitted infection (STI) globally. The data demonstrated a promising dose-dependent decrease in bacterial load in infection as compared to the vehicle control and approved therapy.

In addition to demonstrating capability against different types of bacteria, Recce’s “master key” synthetic antibiotic exhibited efficacy against the Influenza A virus in mice. RECCE 327 showed a significant dose-dependent decrease in the viral growth rate and viral load in lungs for mice infected with Influenza A following treatment with RECCE 327 compared to the control group, and group treated with an approved antiviral drug.

Furthermore, previous in vitro studies treatment with RECCE 327 against S. aureus, E. coli, and P. aeruginosa bacteria showed no resistance, even after over 25 repeated exposures. RECCE 327 continued to display the same clinically relevant kill-rates for standard bacteria and their superbugs forms. This data suggests that RECCE 327 may be more effective against a wider range of bacteria and may come without the toxicity concerns associated with current antibiotics. It also supports RECCE 327’s hypothesized universal mechanism of action for one of the first new class of antibiotics in over three decades.

James Graham was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.