Synthetic Antibiotics Could Improve Treatment of “Superbugs”

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Antimicrobial resistance (AMR) is an increasing cause for concern, with “superbugs” causing over 2.8 million infections in the United States each year. In a study published in the European Journal of Medicinal Chemistry, researchers from the University of Liverpool set out to synthesize highly potent analogs of an antibiotic called teixobactin to improve treatments for drug-resistant infections.

Technology Networks spoke to Dr. Ishwar Singh, a reader in pharmacology and therapeutics at the University of Liverpool and co-author of the study, to learn more about the challenges of drug-resistant infections, the discovery of teixobactin and the benefits of synthetic antibodies.

Kate Robinson (KR): How critical is finding a solution to antibiotic resistance?

Ishwar Singh (IS): Nearly 5 million people sadly lose their lives due to antibiotic resistance-associated infections per year, and millions more live with treatment failure. Therefore, developing innovative antibiotics to tackle resistant bacterial infections is important.

To address this challenge, we aspire to bring new hope to improve and save lives globally by refreshing the antibiotic development pipeline with innovative antibiotics, such as new classes of antibiotics that attack bacteria on multiple fronts.

Our out-of-the-box approach involves one molecule that can target multiple bacterial targets, which is different from the classical approach, which is one molecule, one target.

KR: How are drug-resistant infections affecting the population?

IS: Antimicrobial resistance is labeled a silent pandemic, impacting the population globally. Without action, 10 million people are predicted to succumb to drug-resistant infections each year by 2050, according to the AMR review commissioned by the UK Government in 2014. There are real people behind these numbers.

KR: What is teixobactin and how was it discovered?

IS: Teixobactin is an antibiotic that was discovered in a screen of uncultured bacteria in 2015, and it has been described as a “game changer” in the fight against antimicrobial resistance, given its ability to kill bacteria without detectable resistance, which is associated with its ability to attack bacteria on multiple fronts. It was isolated from soil bacteria that use teixobactin as a chemical weapon to kill other soil bacteria.

KR: Why was a synthetic version of teixobactin produced, and how was this done?

IS: It is important to understand why we need a synthetic version of teixobactin. Drug development has a high attrition rate due to stringent safety and efficacy requirements. A single natural teixobactin is unlikely to reach the clinic due to all these challenges. Therefore, a library of molecules is desirable, however, this is not a viable option for natural teixobactin due to several bottlenecks. Its synthesis is challenging and gives low yields, and it needs a prohibitively expensive and cationic amino acid building block for high potency against multi-drug–resistant bacterial pathogens.

We have simplified the teixobactin molecule by swapping out certain amino acids to reduce the cost and automated the process, speeding up a single coupling step from 30 hours to 10 minutes in high yields. We use commercially available low-cost alternatives, and the cost has been reduced by more than 2000 times, while the efficacy and safety of the molecule has been improved.

Our simplified teixobactins successfully eradicated methicillin-resistant Staphylococcus aureus (MRSA) in mice and were found to accumulate at sites of infection in amounts greater than that required to kill such “superbugs”. We have also demonstrated the scalability at the gram scale, and producing at a larger scale, such as the kilo scale, is possible. All these are important requirements to develop viable antibiotics to address the silent pandemic globally.

KR: Do these analogs have any benefits over the natural molecules?

IS: We have a powerful modular platform based on our disruptive designs, which do not follow the literature.

I feel we have changed the dogma in the field and potentially unlocked the medical potential of a promising new class of potent antibiotics capable of killing superbugs.

Our platform enables synthetic diversity to select or deselect properties and edit the molecules to impact potency and other desirable drug-like qualities that are not accessible through natural teixobactin.

KR: How do you envision teixobactin molecules will be used in a clinical setting?

IS: Our goal is to have a number of viable drugs from our modular synthetic teixobactin platform, which can be used as a “last line of defense” against superbugs to improve and save millions of lives currently lost due to antibiotic resistance-associated infections. Importantly, our synthetic teixobactins killed a wide range of resistant bacteria, such as MRSA taken from human patients, where current antibiotics fail. Moreover, synthetic teixobactins are also stable at room temperature; a cold chain is not required. Therefore, they have the potential to tackle resistant bacterial infections in diverse clinical settings around the world.

Dr. Ishwar Singh was speaking to Kate Robinson, Assistant Editor for Technology Networks.

About the interviewee:

Dr. Ishwar Singh is a reader in antimicrobial drug discovery and development, Department of Pharmacology and Therapeutics and Chemistry at the University of Liverpool. He has a PhD in organic chemistry, biocatalysts, nucleosides, nucleotides and DNA protein interactions from University of Delhi, India. He has 25 Years of experience in organic chemistry focusing on drug design and development, antimicrobials, bioconjugations, biologics delivery, nucleic acids and peptide modifications. He leads several groundbreaking research programs focused on antimicrobial drug discovery and development.