This newsletter is part of a series — here are the links to Part 1, Part 2, Part 3, (this one is Part 4), and Part 5.
Dear All,
We had fun in Feb 2020 discussing whether an antibacterial compound discovered using machine learning was a drug or just a chemical. Building on that conversation, the lab that wrote the original report has a new paper about identification of a narrow-spectrum compound with activity vs. Acinetobacter baumannii. Here are the links you’ll need:
- The first paper: Stokes et al., “A Deep Learning Approach to Antibiotic Discovery,” Cell (2020). DOI: https://doi.org/10.1016/j.cell.2020.01.021.
- 21 Feb 2020 newsletter: “Chemicals Vs. Drugs (Part 1): The End Of Bacitracin / The Buzz Around Halicin”
- 24 Feb 2020 newsletter: “Chemical Vs. Drugs (Part 2): How Do You Discriminate? / More On Halicin”
- 25 Feb 2020 newsletter: “Chemicals Vs. Drugs (Part 3): XKCD Has The Final Word”
- The new paper: Liu et al. “Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii.” Nat Chem Biol (2023). https://doi.org/10.1038/s41589-023-01349-8.
- [4 Feb 2024 addendum]: The group published a further paper on 20 Dec 2023: Wong et al. Discovery of a structural class of antibiotics with explainable deep learning. Nature 626, 177–185 (2024). https://doi.org/10.1038/s41586-023-06887-8.
As a brief recap, that first paper described halicin (homage to the computer HAL in 2001: A Space Odyssey) as a candidate antibacterial. As discussed at the time, available data suggested that halicin was too toxic to be a therapeutic drug.
As we discussed at length in 2020, it’s easy to kill bacteria (steam, fire, and bleach all work) and XKCD (newsletter #3) reminded us that “When you see a claim that a common drug or vitamin ‘kills cancer cells in a petri dish,’ keep in mind that so does a handgun.”
The hard part is selective killing and this has been a challenge since the dawn of the antibiotic era. It was a huge step forward when Ehrlich discovered the toxic arsenicals for syphilis (salvarsan), but this was a VERY toxic therapy (Aside: Please check out the constantly updated “Movies To Discover Antibiotics By!” newsletter and see the discussion of “Out of Africa” for more on the story or salvarsan.) Similarly, the equally toxic arsenical melarsoprol was found useful for Human African Trypanosomiasis (HAT), aka Sleeping Sickness. Penicillin was the safe, easy therapy that replaced salvarsan for syphilis many decades ago, but it was not until recently that fexinidazole did the same for HAT.
But, the idea that machine-based processes might open up new chemical space for discovery of a true antibiotic was (and remains) fascinating. To that end, the paper #2 discusses a compound having narrow-spectrum activity vs. Acinetobacter baumanii. Given the name abaucin, it was identified by a neural network-based approach. It’s actually an old compound (formerly RS102895) that is also known to be an inhibitor of the CCR2 chemokine receptor.
What’s intriguing here is that there are signs of selective antibacterial activity — it is active at 2 mg/L vs. A. baumannii but in active at > 128 mg/L vs. E. coli, P. aeruginosa, and S. aureus. Even better, the authors found a likely mechanism of action (disruption of lipoprotein trafficking). It promoted wound healing when used topically in an artificial wound model and also has a history of having been been given by mouth in a murine model of kidney disease (see cite #20).
That noted, does this make it a drug or even a candidate drug? “No, not yet,” is definitely the answer. Specifically, there are many obvious gaps in terms of knowledge of systemic pharmacology, consequences of chemokine inhibition, and so forth that would need to be addressed before this compound would move beyond the hit stage. For more on the type of work needed, see the Instructions to Authors for Antimicrobial Agents and Chemotherapy for a checklist.
But, it is fascinating to see the progress made by this group in expanding their machine-based discovery tools. And, they are clearly not done. As they write in their conclusions, “In the context of antibiotic drug discovery specifically, future models could be trained on (1) growth inhibition of a pathogen of interest and (2) mammalian cell toxicity” and “forthcoming predictive models can be applied to wide regions of unexplored chemical space, with more confidence that prioritized molecules will satisfy multiple properties that are required of new clinical antibiotics.”
Indeed, indeed .. and wouldn’t it be cool to see the kind of (nearly) Star Trek-like instant creation of new therapies become a real thing? Perhaps one day artificial intelligence can come up with creative solutions to save the day like in in Next Generation’s “Quality of Life” or even become the ultimate medical computer program personified like Voyager’s The Doctor!
We were so very fortunate with the pace of creation of new tools for COVID-19 … to have something similar for bacteria would be extraordinary. The clinical trials would still need to be done, but having a candidate compound in hand is obviously a huge head start!
All best wishes, –jr
John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.
Current funding opportunities (most current list is here)
- The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
- BARDA’s long-running BAA-18-100-SOL-00003 offers support for both antibacterial and antifungal agents. This BAA has offered 4 deadlines/year since 2018 … check the most current amendment for details.
- INCATE (Incubator for Antibacterial Therapies in Europe) is an early-stage funding vehicle supporting innovation vs. drug-resistant bacterial infections. The fund provides advice, community, and non-dilutive funding (€10k in Stage I and up to €250k in Stage II) to support early-stage ventures in creating the evidence and building the team needed to get next-level funding. Details and contacts on their website (https://www.incate.net/).
- These things aren’t sources of funds but would help you develop funding applications
- AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
- The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
- Diagnostic developers would find valuable guidance in this 6-part series on in vitro diagnostic (IVD) development. Sponsored by CARB-X, C-CAMP, and FIND, it pulls together real-life insights into a succinct set of tutorials.
- In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).
Upcoming meetings of interest to the AMR community (most current list is here):
- 6 Jun 2023 (virtual, 2.30-4p BST, 9.30-11.00a EDT): Sponsored by the AMR Industry Alliance, this webinar will be the launch event for the upcoming global Antimicrobial Resistance Certification process that builds on AMRAI’s June 2022 Antibiotic Manufacturing Standard for antibiotic discharge targets. Administered by the British Standards Institute (BSI), this certification process will provide a mechanism for antibiotic manufacturers to demonstrate compliance with the Antibiotic Manufacturing Standard. Go here to register.
- [NEW] 7 June 2023 (virtual, 13.30-15.00 CEST): GARDP-sponsored webinar entitled “Project management in antimicrobial R&D. Go here to register.
- 10 Jun 2023 (Virtual, 3-5.30p India Standard Time): Sponsored by the AMR Declaration Trust, a webinar entitled “Engaging the Pharmaceutical Industry in Joint Efforts to Tackle Antimicrobial Resistance.” Thinking globally and acting locally, this webinar will be a conversation about the global pipeline with a focus on ideas for action in India. Go here to register.
- 3-5 Jul 2023 (Tours, France): 9th Symposium on Antimicrobial Resistance in Animals and the Environment (ARAE). Sponsored by INRAE (French National Research Institute for Agriculture, Food, and Environment, itself a merger of merger of INRA, the French National Institute for Agricultural Research, and IRSTEA, the French National Research Institute of Science and Technology for the Environment and Agriculture), this conference has been running since 2005. Go here for details.
- [NEW] 4-6 Aug 2023 (Bangkok, Thailand): The regional Medical Mycology Training Network Conference by ISHAM’s Asia Fungal Working Group is set to feature both hands-on workshops and clinical sessions for all those managing and working with invasive fungal infections. Go here for details.
- 19-22 Sep 2023 (Boston, USA): ASM-ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. This is an excellent development focused meeting … highly recommended! Go here for details and to register.
- [I am told there a few slots left … get your application in ASAP!] 7-15 Oct 2023 (residential, Annecy, France): ICARe, the Interdisciplinary Course on Antibiotics and Resistance. Now in its 7th year, this course is a deep-dive into the world of antibiotic development. Intense, rigorous, and HIGHLY recommended. Seats are always limited … apply sooner rather than later! Go here for details … final deadline for applications is 21 June 2023!
- [PIPELINE SUBMISSION DEADLINE EXTENDED to 31 MAY] 11-15 Oct 2023 (Boston, USA): IDWeek 2023, the annual meeting of the Infectious Diseases Society of America. Go here for details and to register. Also note that there is a call for IDWeek Pipeline submissions with a deadline of 31 May 2023: “Submit Your Novel Antimicrobial Agents or Diagnostic Technologies: Companies are invited to submit antimicrobials that are in preclinical stages of development (Phase II and III preferred) or were approved after January 2023 for a pipeline session at IDWeek that will include antibacterials, antifungals and antivirals (excluding COVID-19 and HIV). Companies developing novel diagnostic technologies with a minimum of some preliminary proof of concept data may submit as well.”
- 20-23 Oct 2023 (Athens, Greece): 11th TIMM (Trends in Medical Mycology). Go here for details.
- [NEW] 6-7 Feb 2024 (online): Antimicrobial Chemotherapy Conference. This is an annual, free of charge conference that is co-organized by GARDP and the British Society for Antimicrobial Chemotherapy (BSAC). Details to follow — for now, just mark your calendar.
- 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Go here for details.
