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Background:

A new antibiotic, teixobactin, was discovered in 2015 in a screen of uncultured bacteria (using ichip, an isolation chip composed of several hundred miniature diffusion chambers, each inoculated with a single environmental cell, allowing massively parallel cultivation of “uncultivable” species, see doi:10.1128/AEM.01754-09).

Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). It is described as being a promising therapeutic candidate, effective against drug-resistant pathogens in a number of animal models of infection.

It apparently has not yet been approved for clinical use in humans, e.g., see record at NIH. The sponsoring company, NovoBiotic Pharmaceuticals, news posts list several studies. For example, a November 21, 2016 grant from the Bill & Melinda Gates Foundation entitled "Development of orally active analogues of teixobactin" (the 2015 discovery article cited earlier administered teixobactin intravenously to mice). May 7, 2021 a grant from NIAID/NIH was received by NovoBiotic Pharmaceuticals to "further develop teixobactin for treating drug-resistant respiratory infections, as well as investigate other effective routes of administration such as inhalation." (my italics added). April 25, 2023 NovoBiotic was awarded a grant by U.S. Army Medical Research to support "manufacture of GMP material for human trials and includes studies to establish the human dosing regimen."

Question:

I couldn't find any results for the 2016 grant investigating oral administration, nor any discussion of what seems to be holding up clinical testing in humans. Bing suggested that because teixobactin was initially tested intravenously in mice, that it might have to be injected in humans rather than taken orally, however, this is presumably a so-called Artificial Intelligence "opinion," and without any clear scientific or medical justification. Why has teixobactin not been tested orally in humans yet?

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Why has teixobactin not been tested orally in humans yet?

To do drug testing on any drug, you must have a supply of it with which to test. Furthermore, to be useful, it must be reasonably easy to be synthesized. If it can only be made in small batches, at least two things will hamper it's use: it will take astronomical amounts of money to test adequately, and it will be extremely expensive, like, unaffordably expensive. If a drug manufacturer can't sell the product in adequate amounts to cover R&D, it's not going to do so.

As it happens, teixobactin cannot be synthesized easily. In fact, most labs working on it have only been able to make milligrams at a time, because a critical amino acid in the antibiotic is nonnatural and is very difficult to make.

Teixobactin contains a nonnatural amino acid l-allo-End possessing a unique cyclic guanidine moiety, which exists in other natural products, such as mannopeptimycin and enduracidins[6,7]. However, the presence of the unnatural amino acid l-allo-End complicates its total synthesis as reflected in several endeavors from the Payne[8], Li[9], and Chen[10] groups. They achieved the milligram scale total synthesis of teixobactin.

But please take heart. Knowing the structure, the method of action, and the importance of this new antibiotic, many labs are working on finding an effective analog that is more easily synthesized. People aren't ignoring this new drug; they just can't make it in quantities large enough to start human testing. The mouse studies have been quite small, due to the difficulty of producing the drug.

Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics

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Introduction

It is not as surprising as I initially thought (before anongoodnurse widened my perspective with her September 20, 2023 answer and prompted me to study the subject for several weeks) that teixobactin has not been tested clinically in humans yet (2023) for one medical indication or another (a medical indication is a treatment considered proper for a specific diagnosis), regardless of route of administration. I found that it may require on the order of nine years for a new antibiotic to reach the first human Phase I (i.e., human) clinical trial (and funding on the order of 20 million dollars to reach that point, funding which a small biotech drug development company like NovoBiotic must obtain at each step). The discovery of teixobactin was published in 2015, eight years ago as of this writing, so teixobactin is still on the general timeline. To make the following discussion more readable, I will present some acronyms and terms used at the end of the text if elaborating breaks up the text flow excessively (so scan down to check an acronym if necessary).

Antibiotic development stages generally

The following figure, Figure 3 from Walesch, Sebastian, et al. "Fighting antibiotic resistance—strategies and (pre) clinical developments to find new antibacterials." EMBO Reports 24.1 (2023)., provides an overview of the timelines and funding for the stages in the antibiotic drug discovery and development process. In the figure "ca." abbreviates "circa," meaning the numbers are rounded approximations; "M$" means millions of US dollars; costs in the light blue row are mean costs for each stage of a successful project in 2010, while amounts in the darker blue row include costs of attrition and capital:

Figure 3, Walesch 2023; antibiotic develop stages

To clarify the darker blue row costs in the figure (but using numbers from Figure 2 in Paul, Steven M., et al. "How to improve R&D productivity: the pharmaceutical industry’s grand challenge." NATURE REvIEwS| Drug Discovery 9 (2010): 203.), if a company spends 873 million dollars over a 13 year period to bring a new drug to market, investors might ask how much annual return they might have made on that money if they had simply invested in stocks at about the same level of risk as the investment in antibiotic discovery and development. Using 11% as the cost of capital, 873 million dollars out-of-pocket expended over 13 years would amount to a capitalized cost of 1.778 billion dollars.

Consider that researchers might discover a "hit," e.g., some substance that killed a target pathogen, only to find with subsequent testing that the substance was not going to become a true "lead" because, e.g., it was likely toxic to human patients, or was not as effective in vivo, i.e., in a living organism, as it was in vitro, e.g., in a Petri dish with pathogen samples. Because a pharmaceutical company would have to develop many antibiotic drug leads to see one prospective new drug make it to market and profit generation, the attrition rate (the cost of the aborted projects) increases the actual costs from those in the light blue row in the figure to those given in the dark blue row, significantly reducing the ROI (return on investment) from any subsequent profits. This is a large component of why large pharmaceutical companies don't want to get involved with discovering and developing new antibiotics. See the previously cited articles for a comprehensive discussion of the subject.

However,a large pharmaceutical company may join a small biotech company as a deep-pocket, large-resource partner in late-stage clinical phase testing for a new antibiotic that has already cleared the previous stages of development and still appears promising. With funding from public and private agencies who recognize the problem of antimicrobial drug resistance, NovoBiotic is discovering and developing leads with the hope of securing pharmaceutical company partners for the expensive clinical phases down the line (see Lewis, Kim. "The science of antibiotic discovery." Cell 181.1 (2020): 29-45. for a readable discussion of the ongoing AMR or antimicrobial resistance crisis from the perspective of Kim Lewis, one of the discoverers of teixobactin, and a founder of NovoBiotic).

Where does teixobactin appear in the development stages?

Where does the development of teixobactin appear in the stages set out in the figure above? NovoBiotic NovoBiotic Press Releases has several parallel teixobactin lead development processes targeting different medical indications, e.g., anthrax treatment (June 16, 2020 3-year, $3MM SBIR Phase II NIH NIAID grant titled “Teixobactin Development for Anthrax), drug-resistant infections (April 25, 2023 US Army $4,499,475 grant entitled “Late-Stage Preclinical Development of Teixobactin to Treat Drug-Resistant Infections”), tuberculosis (August 30, 2022 $3 million, 3-Year NIAID/NIH grant entitled “Teixobactin Development for Tuberculosis), and a May 7, 2021 $6.2 million, 5-Year NIAID/NIH grant entitled “Developing Teixobactin for Respiratory Infections." Each of those would follow the stages of developing a drug separately in general (including the timelines and costs of the stages described), but benefiting where possible from applicable research in the parallel development processes. All of those are in the pre-clinical stage.

Teixobactin development efforts near Phase I clinical trials?

NovoBiotic was funded by a SBIR (Small Business Innovation Research) award running from mid-2020 to mid-2023 to do preclinical development and testing of teixobactin as an agent against anthrax, with the goal of producing at least 200 grams of CGMP material at a contract manufacturer and being prepared to enter a GLP-compliant, NHP (non-human primates) inhalation anthrax study and a Phase I clinical study in support of FDA approval for treating anthrax under the Animal Rule (a rule which permits FDA to rely on animal studies of efficacy for medical countermeasure development to CBRN when human efficacy studies are not ethical or feasible). Details of the award are at 2020 SBIR award Teixobactin Development for Anthrax and described briefly at NovoBiotic Press Releases: June 16, 2020 - NovoBiotic Pharmaceuticals, LLC was awarded a 3-year, $3MM SBIR Phase II NIH NIAID grant titled “Teixobactin Development for Anthrax."

That SBIR anthrax contract having completed in May (2023), NovoBiotic could be assumed to be looking in the near future to submit an IND (Investigational New Drug application) for this indication. Upon approval of this IND by FDA, Phase 1 clinical trial testing in humans, which in this context (Animal Rule) will involve giving the new drug to healthy volunteers to determine the metabolic and pharmacological actions of the drug in humans (e.g., SAD "Single Ascending Dose" and MAD "Multiple-Ascending-Dose" studies), could begin. Of course, NovoBiotic requires funding for such a Phase 1 study (refer to the figure above, on the order of 15 million dollars generally), so must be soliciting those funds from the public and private agencies available while preparing the IND for the anthrax indication.

How is teixobactin produced in the ongoing studies?

Though teixobactin has been synthesized Karas, John A., et al. "Synthesis and structure− activity relationships of teixobactin." Ann. NY Acad. Sci 1459 (2020): 86-105, the known methods are apparently still too expensive (for various reasons), so NovoBiotic is currently isolating and purifying teixobactin from fermentation (of E. terrae) and have outside contractors (e.g., ACS Dobfar) who can produce large quantities at scale. A 2018 3-year Army grant (Proposal Number: PR170869; Award Number: W81XWH-18-2-0046 ) to NovoBiotic, "Development of Teixobactin to Treat Drug-Resistant Infection," abstract gives more detail about their production methods:

Aim 1. Production of TXB. We first need to make enough TXB to run all the proposed studies. TXB is a natural product produced by a soil microbe (like penicillin and tetracycline). To make TXB, the producing microbe will be grown in liquid cultures (fermentations) that contain growth media. Once the culture achieves sufficiently high microbe densities (approximately 7 days of growth), the TXB will be isolated and purified using standard chemical procedures. We will need about 260 grams of pure TXB to complete the studies, and this work will be performed at NovoBiotic.

To produce enough TXB for eventual human studies and marketing (multiple kilograms of TXB), our production process will need to be scaled-up to a much higher extent than NovoBiotic's capabilities. Therefore, part of Aim 1 will be to develop a manufacturing process with an outside contractor (ACS Dobfar) that has strong expertise with these types of fermentation products. In addition, we will develop analytical procedures to ensure that TXB is produced consistently from batch to batch.

To see the detailed abstract quoted from above, go to CDMRP (Congressionally Directed Medical Research Programs) and select the link at the top of that page Search Awards & Publications. Don't touch any of the search criteria fields except "Proposal Number." Enter "PR170869" (without quotes) and hit enter to obtain the search results for that Proposal Number. Click on the hyperlink returned in a tabular format, it should be blue color "Development of Teixobactin to Treat Drug-Resistant Infections." If you are fortunate, you will then see the Public Abstract I quoted from above. Please note that these kinds of government program acronyms and names and website locations (url's) change frequently, as well as access to the award databases (if it is true "there is nothing hidden that will not be revealed," it seems to require more effort lately).

That award above was also announced (without the extensive abstract above) at NovoBiotic news (see earlier links): October 25, 2018 - NovoBiotic Pharmaceuticals, LLC is awarded a 3-year, $3,584,158 grant entitled “Development of Teixobactin to Treat Drug-Resistant Infections”. That project seemed to have completed satisfactorily since the Army recently made a second award to continue it (go to NovoBiotic news/press releases links previously given above): April 25, 2023 - NovoBiotic Pharmaceuticals, LLC is awarded a new grant entitled “Late-Stage Preclinical Development of Teixobactin to Treat Drug-Resistant Infections”. This work is supported by the U.S. Army Medical Research Acquisition Activity (USAMRAA), in the amount of $4,499,475, through the Joint Warfighter Medical Research Program under Award No. HT9425-23-1-0376.

Conclusion

As of 2023, teixobactin is in pre-clinical stage development for several medical indications, and NovoBiotic is likely preparing an IND application to permit Phase 1 clinical testing for anthrax (under the Animal Rule). Going by the general timelines in our drug development figure above, we might expect to see teixobactin approved for use in particular applications before 2032.

Acronyms and other items not elaborated in the text

ACS Dobfar, Italy. cGMP (FDA and AIFA approved) antibacterials, manufacturing fermentation capacity more than 1300 KL, process set-up in pilot plant. Optimization and scale-up USP and DSP.

CBRN chemical, biological, radiological, or nuclear threats

CGMP Current Good Manufacturing Practice: FDA regulations to assure proper design, maintenance, monitoring, and control of manufacturing processes and facilities applicable to all drugs, for humans as well as animals. You may see this written as cGMP also.

FDA Food and Drug Administration, enforces laws enacted by the U.S. Congress (the Federal Food, Drug, and Cosmetic Act and related statutes) and regulations established by the Agency (primarily section 21 of the CFR or Code Of Federal Regulations) to assure drugs are safe and effective for their intended uses.

GLP Good Laboratory Practice: a managerial quality control system covering the organizational process and the conditions under which non-clinical, i.e., not including human subjects, health and environmental studies are planned, performed, monitored, recorded, reported and retained. See OECD Principles of Good Laboratory Practice.

NIAID National Institute of Allergy and Infectious Diseases

NIH National Institutes of Health

TXB teixobactin

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