It is an honour to receive an award named after Prof. Satoshi Ōmura, the 2015 Nobel Laureate and Japanese microbiologist renowned for his discovery of avermectins, which led to the development of ivermectin—a breakthrough that has transformed global health by combating parasitic diseases such as river blindness and lymphatic filariasis. His pioneering work at Kitasato University, Tokyo, exemplifies the power of natural product research in saving millions of lives.
Flightpath Biosciences has begun human clinical testing for FP-100 (hygromycin A), which has potent activity against several spirochete Gram-negative bacteria such as Borrelia burgdorferi (Lyme disease) and Treponema pallidum (syphilis). Other spirochete-driven diseases include yaws (T. pallidum pertenue), advanced periodontal disease (T. denticola), and leptospirosis (Leptospira spp.). Spirochete bacteria have non-standard outer membranes compared with typical Gram-negative bacteria. These consist of an outer phospholipid bilayer (enriched in phosphatidylcholine and phosphatidylglycerol, lacking lipopolysaccharide (LPS)) with abundant lipoproteins such as OspA and OspC.
Hygromycin A was first discovered in the 1950s but overlooked due to the era’s focus on broad-spectrum antibiotics. Hygromycin A inhibits bacterial protein synthesis via ribosomal 23S rRNA binding and its structure is not currently represented in approved antibiotics. Several research programs have investigated hygromycin A analogues, including a Pfizer program that reported a more potent analogue CE-156811 in 2011, but none have made it clinical trials.
Structures of hygromycin A and synthetic analogue CE-156811, along with stylised picture of a tick with a tablet (created by Grok and MSB)
Using bioassay guided isolation to identify compounds with selective activity against B. burgdorferi over Staphylococcus aureus, Kim Lewis’s team at Northeastern University rediscovered hygromycin A (published in Cell in 2021). Promisingly, it showed in vitro and in vivo activity against B. burgdorferi. In addition, hygromycin A does not disrupt the growth of beneficial gut bacteria, unlike current treatments such as doxycycline. It was also shown that hygromycin A enters the bacterium via a nucleoside transporter, which is not present in most other bacteria. Flightpath Biosciences licensed hygromycin A in 2021 and a phase I trial (ACTRN12623001153606) was completed in March 2025 (results pending).
In North America and Europe, Lyme disease is caused by the B. burgdorferi sensu lato complex (including B. burgdorferi sensu stricto, B. afzelii, and B. garinii), transmitted by Ixodes ticks. Diagnosis is based on characteristic symptoms, history of exposure, and serology/PCR. Lyme disease affects an estimated 476,000 people annually in the U.S. alone, with up to 20% of patients experiencing persistent symptoms due to treatment limitations. However, in other countries such as Australia, where B. burgdorferi is not endemic, there is debate about what causes “Lyme-like illness”. Some Australians who have not travelled internationally develop chronic, multi-system illnesses after tick bites, but the cause is uncertain.
In conclusion, with its B. burgdorferi (spirochete) and microbiome-sparing selectivity, hygromycin A (FP-100) represents a promising advance in the treatment of Lyme disease. Its development highlights the value of continually revisiting natural products to address persistent global health challenges.
“Opening”. Imagine waking up exhausted, struggling to breathe at night, and disrupting your partner’s sleep. For millions with Obstructive Sleep Apnea (OSA), this is reality. AD109, a once-daily oral therapy that combines the selective norepinephrine reuptake inhibitor atomoxetine with the antimuscarinic agent aroxybutynin, is being developed by Apnimed and has now delivered compelling Phase III results (also see recent commentary). With many patients struggling to tolerate CPAP masks, an effective oral pill could offer a welcome and transformational alternative.
How AD109 Compares to Emerging OSA Treatments:
● Zepbound (tirzepatide): Approved for OSA in obese patients, effective with CPAP but reliant on weight loss, limiting its use for non-obese individuals.
● Sunosi (solriamfetol): Targets daytime sleepiness in OSA but doesn’t address airway obstruction.
● Orexin Antagonists (e.g., lemborexant): In early development for insomnia, with unproven efficacy in OSA
Unlike these, AD109 directly targets the neuromuscular cause of OSA, offering a non-invasive, weight-independent solution.
Closing Thought. As a potential first-in-class therapy, AD109 could redefine OSA care with a convenient oral solution. If approved, it may offer a broadly accessible alternative to CPAP or weight-dependent drugs.
🧪 Exploring how natural product chemistry can trigger unexpected occupational skin reactions
As someone passionate about natural products and workplace safety, I’ve always been mindful of autoxidation—and I recently discovered it’s responsible for turpentine dermatitis. This skin reaction results from exposure to turpentine, a solvent derived from pine resin commonly used in paints, varnishes, and cleaning products.
❓ What is Turpentine Dermatitis?
This condition typically presents as irritant contact dermatitis (redness, itching, scaling) or, in some cases, allergic contact dermatitis (blistering, swelling), following direct contact with turpentine or its vapours. While it’s less common today due to safer alternatives, it remains a risk for painters, artists, and industrial workers. Prevention involves protective gear, proper ventilation, and immediate washing of skin after exposure.
🔬 What is Autoxidation and The Role of Monoterpene Hydroperoxides?
A key culprit in allergic reactions is monoterpene hydroperoxides (ref. 1), formed when components of turpentine (such as Δ-3-carene, Figure 1) oxidise upon exposure to air or light—a process known as autoxidation (ref. 2). In natural products research, we often isolate the corresponding reduced alcohols. These hydroperoxides are potent skin sensitisers, triggering immune responses that cause severe itching and inflammation. They may also act as irritants, worsening skin damage. To minimise oxidation, turpentine should always be stored in airtight, dark containers.
Figure 1. Autoxidation products of the major monoterpene, (+)-3-carene, in many turpentines (Image made by Grok and MSB)
💡 Why It Matters…
● Although turpentine use has declined, monoterpene hydroperoxides remain relevant in essential oils and pine-derived products, posing ongoing risks for sensitisation.
● Whenever natural products with allylic alcohols or peroxides are isolated, consider the possibility that they are autoxidation products. Also be mindful of autoxidation during storage—store potential candidates under argon and in the dark where possible.
References
1. One hundred years of allergic contact dermatitis due to oxidized terpenes📘Contact Dermatitis, 2021, 85: 627–636 🔗 https://doi.org/10.1111/cod.13962
2. Autoxidation vs. antioxidants – the fight for forever 📘Chemical Society Reviews, 2021, 50: 7343–7358 🔗 https://doi.org/10.1039/D1CS00265A
🦠 Since the introduction of penicillins in the 1940s, β-lactam antibiotics have been a cornerstone of modern medicine. However, bacteria quickly fought back by producing β-lactamase enzymes that degrade these antibiotics before they can exert their effect. To overcome this, β-lactamase inhibitors (BLIs) were developed to be co-administered with β-lactam antibiotics, protecting them by irreversibly binding and inactivating β-lactamase enzymes — thereby restoring the antibiotics’ ability to target penicillin-binding proteins (PBPs) and kill the bacteria.
⚙️The discovery of the first BLI, clavulanic acid from Streptomyces clavuligerus, was a key breakthrough. Most people have been prescribed Augmentin®, the combination of amoxicillin and clavulanic acid that has been in use since 1981. This was followed by synthetic inhibitors like sulbactam and tazobactam, introduced in the mid-1980s and early 1990s respectively. More recently, two new classes of non-β-lactam inhibitors, diazabicyclooctanes (DBOs) and boronates, have been developed.
💡Fast forward to the approval in February 2024 of a new BLI/β-lactam combination: enmetazobactam + cefepime (marketed as Exblifep®) has now been approved in the USA, Europe, and India for the treatment of complicated urinary tract infections (cUTIs). The enmetazobactam story began in India, where researchers at Orchid Research Laboratories identified that adding a methyl group to the triazole ring of tazobactam created a zwitterionic BLI. This small chemical change dramatically improved bacterial penetration and pharmacokinetic properties. Allecra Therapeutics (headquartered in Germany with operations in France) led the clinical development.
Structures of clavulanic acid, tazobactam, enmetazobactam; background image created by myself and Grok showing lysed and un-lysed bacteria
🌟 Enmetazobactam is a great example of how thoughtful chemical modifications, combined with an understanding of resistance mechanisms, can deliver clinical impact.
Continuing on my blog posts on natural products, antibiotics and other topics…
💠 During World War II, both Allied and Axis forces used stimulants like amphetamine and methamphetamine to maintain alertness in combat. But another related compound—fenethylline, better known as Captagon—has taken a darker path in recent decades. Amphetamine ties back to natural products through the exploration of chemistry around ephedrine, originally isolated from Ephedra sinica in the 1880s. I will expand upon this link in a later blog.
💠 Developed in the early 1960s, fenethylline is a co-drug of amphetamine and theophylline, joined by an ethane bridge. It was originally prescribed for hyperkinesis (now ADHD), narcolepsy, and depression, often preferred over amphetamines for its more tolerable profile. Its clinical use was short-lived, however—it was banned in most countries by 1986 following WHO’s inclusion under the Convention on Psychotropic Substances.
💠 Pharmacologically, fenethylline is more lipophilic, enabling rapid absorption into the CNS. It metabolises into amphetamine (24.5%) and theophylline (13.7%, caffeine related compound), working synergistically: amphetamine boosts dopamine signalling as a potent stimulant, while theophylline provides weaker stimulation and bronchodilation.
💠 Though long out of medical use, fenethylline re-emerged on the black market, produced in clandestine labs across the Middle East and Southern Europe. It has since been linked to recreational and combat use—highlighting drug misuse in modern conflict zones.
🧪 This is a potent example of how drugs can be redirected far from their original therapeutic intent.
MSBChem Consulting 