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.

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.

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