The world’s microbes have not run out of ways to fight bacteria. Antibiotic hunters may simply have been searching the same familiar territory—and overlooking what happens after a promising molecule is found. That is the central message of a review by Ahmed Hamed, PhD, and Zeinab Khalil, PhD, both at the University of Queensland. The researchers describe “microbial dark matter” as organisms that resist conventional cultivation, along with silent biosynthetic pathways in familiar microbes that could encode undiscovered natural products.
The stakes are considerable. Antimicrobial resistance directly caused an estimated 1.27 million deaths worldwide in 2019, according to figures cited in the review. Yet traditional screening has repeatedly mined the same microorganisms, particularly Streptomyces, often rediscovering known compounds rather than uncovering new antibiotic structures.
Genome-mining tools now identify biosynthetic gene clusters (BGCs)—groups of genes responsible for producing specialized molecules—even when those products never appear in laboratory cultures. Metagenomics extends the search to microbes that scientists cannot grow, while devices that recreate natural environments can bring some previously inaccessible organisms into cultivation.
Consider teixobactin, an antibiotic discovered from Eleftheria terrae, a soil bacterium recovered using an iChip device that cultivates microbes in their native environment. Although teixobactin shows activity against several Gram-positive pathogens, its producer remains difficult to grow conventionally. The review highlights the ongoing reliance on chemical synthesis to supply the compound.
“Detection, however, is not production,” the researchers write. An analysis of 50 studies cited by the authors found that large-scale attempts to express natural-product pathways in alternative microbial hosts produced detectable compounds only 11–32% of the time. Missing genes, inadequate precursor supply, product toxicity, and poor fermentation performance can all stall development.
The review makes bioprocess engineering central to the solution. In one cited study, adding talc microparticles to an engineered Streptomyces culture increased production of pamamycin nearly threefold, from 18 to 50 mg/L. Reworking pathway regulation, engineering microbial production hosts, and optimizing culture conditions offer other routes to better yields.
Artificial intelligence could help researchers choose which clusters deserve attention by connecting genomic and molecular features to predicted biological activity. But predictions still require experimental confirmation, and abundant material is needed to study a promising compound’s mechanism and development potential.
Rather than bet on any single platform, Hamed and Khalil envision an iterative workflow linking ecological sampling, genome and metabolome analysis, activity testing, target identification, and scalable production. The next antibiotic breakthrough, their review suggests, will depend as much on making a molecule as on finding it.
