Engineering the future of antibiotics

In the ongoing battle against antimicrobial resistance, scientists are exploring innovative approaches to develop new antibiotics capable of tackling the ever-evolving threat of drug-resistant bacteria. One such development is the emergence of polymeric antibiotics, a new class of compounds that show some promise in the fight against bacterial infections.

Before antibiotics became widely available in the 1940s, infectious diseases posed a significant threat to public health, with an average life expectancy for humans of just 47 years at birth in even the most industrialised nations. The discovery of antibiotics has made many previously dangerous or deadly diseases easily treatable. It has enabled much of modern medicine, from surgery to chemotherapy to organ transplants.

However, as bacteria have evolved to resist the effects of these drugs, antimicrobial resistance has become a grave global concern. It is estimated that by 2025, drug-resistant infections will claim the lives of 10 million people annually, equivalent to the current death toll from cancer.

“It’s a serious issue, and scientists are looking at alternative ways to kill bacteria,” says Dr Shu Lam, head of business development at Linear Clinical Research.

A new generation of antibiotics

Ongoing chemistry research has enabled scientists to create a new class of compounds that can fight bacteria. They’re known as “antimicrobial polymers,” and are synthetic substances composed of large molecules, each consisting of multiple repeating units of simpler chemical structures. Researchers drew inspiration from antimicrobial peptides, also called “host defence peptides” (HDPs), a type of small protein and part of the innate immune response that defend the body against harmful invaders.

HDPs are relatively small, typically composed of 10 to 50 amino acids that confer water solubility and charge-carrying properties, allowing them to attach to bacterial membranes. Their antimicrobial action involves disrupting bacterial cell walls or triggering immune responses.

Natural and synthetic HDPs have proven effective against bacterial infections but have limitations, says Lam, who has spent several years studying antimicrobial polypeptide particles to treat multidrug-resistant bacteria. Peptides are susceptible to degradation in the bloodstream, are expensive to synthesise, and have constraints on the number of amino acids that can be joined in a sequence-defined manner.

“Antimicrobial peptides can be highly specific and effective,” says Dr Lewis Blackman, the Drug Discovery Chemistry Team team leader within CSIRO Biomedical Manufacturing. “But they can be rapidly cleared from the bloodstream and, in some cases, stick to proteins in the blood, reducing their effectiveness.”

In contrast, polymeric antibiotics offer several advantages that make them an exciting area of research. “One of the holy grails for polymer science is the ability to use low-cost monomers and processes to make polymers of different architectures and lengths while also having perfect sequence and length control,” says Blackman.

Playing with structure for precision

Researchers can manipulate the size and structure of polymeric antibiotics to enhance their selectivity for certain types of bacteria, offering a targeted approach to treatment. This precision in targeting holds great promise for addressing bacterial infections with greater specificity and efficacy.

Researchers have experimented with various structural modifications, including sequence control, assessing whether block structures or statistical distributions offer superior antimicrobial activity. They can play with factors like how big the polymer is, whether it’s a linear chain or branched like a star, whether it self-assembles to make 3D structures or attaches active components to tune antimicrobial activity.

One key advantage of polymeric antibiotics lies in the inherent differences between bacterial and mammalian cell membranes. Bacterial membranes exhibit distinct structural and charge differences compared to mammalian cell membranes. Scientists have used these differences to create polymers that are selectively attracted to bacterial membranes via electrostatic interactions, with minimal impact on healthy mammalian cells.

Recent advances in nanotechnology have further expanded the potential of antimicrobial polymers. Nanoparticles have demonstrated broad-spectrum antimicrobial activity against various pathogens, including bacteria, viruses, fungi, and more. They can disrupt microbial cell membranes, induce intracellular antimicrobial effects, interact with bacterial DNA and proteins, inactivate bacterial enzymes, and interfere with biofilm formation.

Nanoparticles are also effective cargo carriers, capable of transporting and releasing antimicrobial molecules within bacteria. They can be highly specific and biocompatible, with a high potential for synergistic therapy where two or more drugs are administered simultaneously.

Opposing the resistance

Unlike conventional antibiotics, which primarily target specific metabolic pathways within bacteria, polymeric antibiotics employ a multi-pronged attack strategy that has yet to be entirely understood. They target bacterial cell membranes primarily, but some research has shown that they can infiltrate bacterial cytoplasm and interact with bacterial DNA and other metabolic pathways. “The broad-spectrum approach makes it difficult for bacteria to develop resistance, even when exposed to low doses of the polymer multiple times and over a long period of time,” says Lam.

Recce Pharmaceuticals, an Australian company developing synthetic polymers to treat infections, including sepsis, burn wound infections, and urinary tract infections, has developed a polymer known as “R327,” which irreversibly disrupts the production of adenosine triphosphate (ATP), the primary source of energy for bacterial cells. “It’s a universal mechanism of action,” says Michele Dilizia, Chief Scientific Officer and Executive Director at Recce Pharmaceuticals. “No matter how much bacteria change, we’ve got the master key.”

Recce is now testing R327’s safety in the phase I clinical trial for urinary tract infection and phase I/II for topical application on infected diabetic foot ulcers. “The road ahead is very promising,” says Dilizia.

Overcoming hurdles in clinical translation

As researchers continue to explore the potential of polymeric antibiotics, a critical question remains: can these materials transition from the laboratory to the clinic? The journey from bench to bedside involves assessing in vitro and in vivo toxicity, biocompatibility, cell viability, biodistribution, and immunogenicity. These factors are pivotal in determining whether polymeric antibiotics will become a reality in clinical practice.

Many polymers have demonstrated antimicrobial activity in the lab, but the road to the clinic is rugged. These polymers are often tricky to prepare and hard to administer. They can be toxic to human cells and good bacteria and cause damage to the liver or the bladder where they end up. “The main issue with polymers is never antimicrobial activity. We know they are effective,” says Lam. “One of the primary challenges is ensuring their safety when introduced into the human body.”

“For something to go into a human, it needs to be really clearly defined and well characterised,” says Blackman. “With a polymer, it is somewhat more challenging because you’re usually working with distributions rather than specific entities.”

While the road ahead may be challenging, ongoing research and advancements in understanding these materials and their interactions with bacteria offer hope for the future.

This is just one solution to antibiotic resistance. Manuela Callari explores many more in her feature for Issue 100 of Cosmos Magazine. To read it online or in print, subscribe to the magazine or become a My Cosmos member.