A patent has been filed, and the researchers are working with the U.S.-based pharmaceutical company Hsiri Therapeutics to license the compound.

When viruses make bacteria tougher

A second avenue is phage therapy, which uses viruses called bacteriophages. These viruses infect bacteria, hijack their replication machinery and multiply until the bacteria burst open.

But M. abscessus can push back, as researchers from NTU's Lee Kong Chian School of Medicine and the Agency for Science, Technology and Research (A*STAR) discovered. The bacterium comes in two variants: a smooth form, coated with lipids called glycopeptidolipids, and a rough form that lacks them. The rough variant causes more severe disease and is harder to treat.

When the scientists treated smooth strains with phages that target them, rough variants emerged. These carried mutations in genes responsible for building and transporting glycopeptidolipids to the bacterial surface. The researchers hypothesize that losing these surface lipids prevents phages from binding and attacking. Other bacteria became phage-resistant while staying smooth, acquiring mutations in different surface-related genes instead.

"These findings reveal an important challenge in developing phage-based therapies," explains Professor Pablo Bifani of LKCMedicine, the study's corresponding author. "Although phages can effectively eliminate bacteria, they may also inadvertently make infections more difficult to treat, as seen in the 'rough' form."

He adds that a cocktail of phages targeting both smooth and rough variants could reduce the likelihood of resistance developing during treatment.

A microscopic speargun, decoded

The third study concerns Pseudomonas aeruginosa, a highly drug-resistant pathogen that causes chronic infections in immunocompromised, hospitalized and critically ill patients. Its signature weapon is the Type VI Secretion System (T6SS), which works like a speargun, injecting toxins into rival bacteria and host cells to clear the way for colonization.

Researchers at NTU and Imperial College London, using biochemical analysis and cryo-electron microscopy, worked out how this weapon loads its ammunition. A protein called Hcp first captures a toxin. Five more Hcp proteins then wrap around it to form a ring resembling a flying saucer, with the toxin at its center; larger toxins may require two rings. The loaded rings stack into a tube, and when the system contracts, it propels that tube outward like a harpoon into the target cell.

Because the tube can carry different toxins at once, a single shot can deliver a cocktail of harmful compounds.

"This bacterium does not just fire a single toxin," says co-corresponding author Professor Alain Filloux, research director of the Biofilms & Health Cluster at NTU's Singapore Center for Environmental Life Sciences Engineering. "It loads a cocktail of toxins into a microscopic speargun and fires them in one strike, allowing it to attack different targets, including beneficial bacteria that normally live in the body, as well as the host's own defense cells."

Blocking this loading step, he suggests, could disarm the bacterium and make it less able to cause disease. The researchers also note that harmless bacteria could be engineered to carry a T6SS loaded with toxins against invading pathogens, including resistant gut bacteria.

"What is exciting about this work is that we can now see, at near-atomic detail, how a bacterial toxin is physically captured and enclosed inside the building blocks of the T6SS," says Associate Professor Tiago Dias da Costa of Imperial College London, who co-led the study. "High-resolution 3D images obtained from cryo-electron microscopy reveal that toxin loading is not a passive process, but a highly organized assembly pathway in which the secretion tube forms around its cargo."

Early promise, open questions

All three studies remain at an early stage, and the findings come largely from laboratory experiments rather than clinical trials. The anti-M. abscessus compound's effectiveness has so far been demonstrated in combination with clofazimine in preclinical settings, and the proposed phage cocktails and T6SS-blocking strategies are still concepts that require validation. Still, by mapping how resistant bacteria generate energy, evade viruses and load their weapons, researchers have identified concrete molecular targets — and new ways to stay one step ahead.