Challenges and Opportunities for Bioactive Compound and Antibiotic Discovery in Deep Space

Long-term space habitation for exploratory missions or colonization will involve significant health risks to astronauts living in enclosed habitats in altered gravity, for years at a time with no resupply from Earth [Taylor and Sommer (Int J Antimicrob Agents 26:183–187, 2005)]. Permanent bases on Mars, in deep space, and on the moons of Jupiter and Saturn may one day be established, putting space colonists far out of the reach of terrestrial material or medical aid. Microgravity, low oxygen levels and radiation exposure greatly increase cellular oxidative stress and mitochondrial dysfunction, bone and muscle loss, cancer risk, central nervous system dysfunction, and a whole host of other issues for which our Earth-based evolutionary lineage has not prepared humanity [Afshinnekoo et al. (Cell 183:1162–1184, 2020); Patel et al. (NPJ Microgravity 6:33, 2020)]. All of these issues, along with potential malnutrition and the psychological stress of confinement with a limited number of individuals [Oluwafemi et al. (Life Sci Space Res 28:26–31, 2021)], and without access to the natural world, inevitably will lead to decreased immune function, making astronauts more vulnerable to infection by secondary pathogens which normally operate as human commensals (not to mention primary pathogens that can infect healthy individuals). Although on Earth the shelf life of many medications including antibiotics is much longer than previously thought, these medications degrade much more rapidly in the high-radiation environment of space [Du et al. (AAPS J 13:299–308, 2011); Blue et al. (NPJ Microgravity 5:14, 2019)]. Astronauts on long-term missions, or colonists on other planets, will likely need to be able to manufacture life-saving drugs in situ. In particular, if unforeseen antimicrobial-resistant pathogens emerge in space habitats which are not treatable with current antibiotics, new antibiotics will need to be developed. This is one problem that cannot be solved entirely remotely, as the antibiotics must be tested against the pathogen in question. Most antibiotics used on Earth are natural products derived from microbes, or synthetic variants thereof; future space colonists will need to make use of the biodiversity of their space habitats and mine the ecological relationships between whatever microbial species they bring with them. Tools for antibiotic discovery must also be created or adapted for use in the space environment. Examples are methods for studying minimum inhibitory concentrations for different microbial interactions in space, and producing databases of the whole genome sequences of common isolates from space stations such as the International Space Station (ISS) for genome mining of biosynthetic gene clusters and potential mechanisms of antimicrobial resistance. Other technology needs are building space-hardy liquid chromatography-mass spectrometry (LC–MS) platforms to link to molecular networking tools, and designing provisions for fermentation, extraction and purification of antibiotic compounds, which must be developed long before a mission to Mars or beyond is planned in order to benchmark the processes. Whole genome sequencing and a full genetic inventory of microbes isolated from the ISS is already underway [Be et al. (Microbiome 5:81, 2017); Singh et al. (Microbiome 6:204, 2018); Checinska Sielaff et al. (Microbiome 7:50, 2019); Simpson et al. (Microbiol Resource Announc 10:e00751–e1721, 2021); Simpson et al. (Microbiol Resource Announc 10:e00751–e1721, 2021); Urbaniak et al. (Microbiome 10:1–19, 2022)], and soon isolated bacteria and fungi aboard the ISS may be sequenced in situ [Stahl-Rommel et al. (Genes 12:106, 2021)]. The process of novel bioactive compound prospecting in space will be difficult without the biodiversity of Earth, or all the many tools of a fully equipped lab in full gravity. However, there are many potential advantages as well, including the ease of purification and crystallization of protein compounds in microgravity [Borgstahl et al. (Perfect crystals: microgravity capillary counterdiffusion crystallization of human manganese superoxide dismutase for neutron crystallography, 2022); Martirosyan et al. (npj Microgravity 8:1–12, 2022)], the focus and attention of many scientific minds such an endeavor would bring in response to a space health problem, and the lack of a need to provide a business case which currently bottlenecks antibiotic discovery and production (Miethke et al. [Nat Rev Chem 5:726–749, 2021)]. A first step in this process is creating a framework for addressing the general ecology of a future space habitat microbiome—do unplanned consortia of microbes in microgravity form complex ecosystems capable of outcompeting pathogenic microbes? (Fig. 1) And further, can these microbial consortia be used for new drug discovery on space missions where resupply from Earth is not possible? Or will the biodiversity of such a habitat, mission or colony be low enough that a pre-planned selection of preserved microbes or extremely diverse environmental samples such as soils should be brought along?

Strategies for future antibiotic discovery in space.