Breathing New Life into Old Medications

By Gregory Mario, MBA, President and CEO, TAXIS Pharmaceuticals

Antibiotic resistance – or antimicrobial resistance (AMR) – has been making headlines for decades, but the problem may go back even further than many of us realize.

“The first sign of antibiotic resistance became apparent soon after the discovery of penicillin. In 1940, Abraham and Chain reported that an E. coli strain was able to inactivate penicillin by producing penicillinase,” according to a 2017 paper in the Yale Journal of Biology and Medicine. What’s more, “The development of resistance went hand in hand with the introduction of new generations of penicillin into clinical practice.”1

Of course, the problem doesn’t stop with penicillin. “More than 150 antibiotics have been found since the discovery of penicillin, and for the majority of antibiotics available, resistance has emerged,” the paper’s authors note.1 “Moreover, the recent rise of multi/pan-drug resistant strains has correlated with enhanced morbidity and mortality. Overall, ineffectiveness of the antibiotic treatments to ‘superbug’ infections has resulted in persistence and spread of multi-resistant species across the globe. This represents a serious worldwide threat to public health.”1

And calling AMR an epidemic is not hyperbole; researchers have found that “as many as 10 million people a year could die by 2050 due to the failure of prescription drugs, as viruses, bacteria, and other pathogens evolve to evade them, and science fails to keep up.”2 Additionally, AMR may cost $100 trillion or more globally by the same year – a figure that takes into account healthcare costs, lost productivity, and other factors.2

All Living Organisms Want to Survive

Society at large learned a lot during the height of the COVID-19 pandemic about how viruses mutate and evolve to survive. Bacteria that cause conditions like staph infections and pneumonia have the same primary objective – stay alive.

In general, antibiotics are designed to target specific parts of a bacteria’s structure or cellular machinery.3 But, like viruses, bacteria can mutate, evolve, and reproduce rapidly to survive attacks from antibiotics.3

Some of the methods bacteria have for surviving antibiotics include basic survival of the fittest (those most susceptible die off, leaving the stronger, more resistant bacteria to reproduce), random mutation of bacterial DNA that results in genetic changes that make bacteria more resistant, or DNA exchange, where antibiotic-resistant genes from one type of bacteria may be incorporated into other bacteria.3

Two common mutations researchers have seen in bacteria that contribute to AMR include development of “pumps” that can remove the antibiotic molecule before it reaches its target, and the production of enzymes that can inactivate antibiotics.3

So, what can we do about it?

Fighting Back Against Bacteria’s Defenses

At TAXIS Pharmaceuticals, we have been working since 2009 on the development of compounds that combat antimicrobial resistance. We have several investigational products for this purpose in pre-clinical and clinical development, and recently received a significant grant from the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Disease (NIAID) to continue research and development of our efflux pump inhibitors (EPIs).

Bacterial efflux pumps act like bilge pumps, flushing antibiotics out of the bacterial cell, and are responsible for antibiotic resistance in many gram-negative strains. TAXIS Pharmaceuticals’ investigational EPIs are compounds which, when delivered in combination with already-approved antibiotics, are intended to neutralize the bacterial cellular processes that cause antibiotic resistance, enabling the antibiotics to be effective in fighting off the bacteria they target.

Now, the recently announced NIH grant – for up to $3 million over three years – will allow us to complete pre-clinical research on the first of our EPIs. Specifically, the grant will be used to complete lead optimization of our first EPI agent in combination with the antibiotic levofloxacin, which is commonly used to treat deadly Pseudomonas aeruginosa infections.

Pseudomonas aeruginosa can cause hospital-acquired pneumonia (HAP) and a subset of that condition, ventilator-associated pneumonia (VAP). HAP is the most common healthcare-associated infection in the United States and can result in high morbidity and mortality rates and substantial healthcare costs.

This grant is an incredibly important milestone on the path to developing our EPIs and beginning first-in-human clinical trials. The implications of restoring the potency and efficacy of antibiotics are huge – for patients, society, payers, and manufacturers.

Hope for the Future

Combating antibiotic resistance around the globe is without a doubt a huge undertaking. To date, all antibiotics have over time lost effectiveness against their targeted bacteria,3  AMR is the world’s third most lethal condition when compared to infectious diseases, coming in behind only and tuberculosis, depending on the year,2 and the World Health Organization has reported that “the clinical pipeline of new antimicrobials is almost dry.”4

Yet, we feel hopeful that all is not lost. With enough companies and enough scientists devoting their energy, expertise, and resources to the problem, we believe we can find a sustainable, long-term solution to this challenge. And while we’re excited to continue development of our investigational EPI compounds with the NIH grant resources, that’s only the beginning of our efforts. We’re taking a three-pronged approach to combating AMR that involves developing additional compounds with other mechanisms of action, including targeting proteins within bacterial cells that are responsible for cell division and inhibiting dihydrofolate reductase (DHFR), an enzyme within bacterial cells that is involved in the synthesis of raw material for cell proliferation.

We have high hopes that, over time, we will be able to breathe new life into old antibiotics and save lives.

To learn more or discuss partnership or investment opportunities, contact us today.

References:

  1. Lobanovska M, Pilla G. “Penicillin’s Discovery and Antibiotic Resistance: Lessons for the Future?” Yale J Biol Med. 2017 Mar 29;90(1):135-145. Accessed March 6, 2024.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369031/#:~:text=The%20first%20sign%20of%20antibiotic,by%20producing%20penicillinase%20%5B20%5D
  2. Prater, Erin. “Failure of Some Prescription Drugs Could Kill 10 Million Annually by 2050.” Fortune. 17 Jan. 2024. Accessed March 6, 2024. https://fortune.com/well/2024/01/17/antimicrobial-resistance-antiobiotic-amr-could-kill-10-million-annually-pandemic-world-economic-forum-davos/
  3. Missouri Department of Health & Senior Services. “What is Antibiotic Resistance?” Accessed March 6, 2024. https://health.mo.gov/safety/antibioticresistance/generalinfo.php#:~:text=Through%20mutation%20and%20selection%2C%20bacteria,enzymes%20to%20inactivate%20the%20antibiotic
  4. World Health Organization. “Antimicrobial Resistance Fact Sheet.” 21 Nov. 2023. Accessed March 6, 2024. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance