Antibiotic resistance continues to be a huge concern for both human and animal health practitioners. One study estimated that by 2050, 10 million people will die every year due to drug-resistant infections [O’Neill J. Tackling drug-resistant infections globally: Final report and recommendations. Review on Antimicrobial Resistance 2016]. Researchers are actively looking into other antimicrobial possibilities. Living in the guts of parasitic worms and insect larvae are two potential bacterial groups that might be a source for new antimicrobial drugs: Photorhabdus and Xenorhabdus [Front. Microbiol. 18 Dec 2019, vol 10; https://doi.org/10.3389/fmicb.2019.02893; and Drug Discovery News.com Dec/Jan 2023, vol. 8, issue 12].
The parasitic worms currently identified live in soil in Thailand. The two microbes flourish in the worm guts, but only one microbe species is present at any given time. The microbes don’t do much until their worm host infects an insect larva. Once burrowed into the larva, the worm “spits” the microbe into the larval hemolymph, whereupon bacterial toxins are produced and released, which end up killing the insect larva to provide a meal for the parasitic worm.
Here’s where it gets interesting: A dead larva is a magnet for other soil bacteria, nematodes, fungi, and other soil insects because of its availability as a food source. In order to protect the insect cadaver from being consumed by species other than the parasitic worm, the bacteria produce a toxic cocktail of antibiotics and antifungal molecules to kill those invaders before they can colonize the dead larva. The promising feature of this symbiosis between gut-residing bacteria in parasitic worms and their infusion into insect larva is that the secondary metabolites produced by the microbes have the potential for human and veterinary applications. The antibacterial “natural products” produced by the worm gut microbes kill other microbial organisms (poised to eat the dead larva) while not having any adverse effect on the parasitic worm host.
The researchers have identified at least 1,000 of these natural products thus far. Extracts from two different Photorhabdus species have been shown to inhibit multidrug-resistant Acinetobacter strains as well as two strains of MRSA (methicillin-resistant Staphylococcus aureus). The researchers are currently trying to identify how the compound kills drug-resistant bacteria. Both Photorhabdus and Xenorhabdus can be grown in the laboratory and can be stimulated to produce and release their antimicrobial molecules. One compound identified that has antibacterial activity is called “odilorhabdins,” which targets bacterial ribosomes to interrupt bacterial translation. Pharmaceutical scientists have been able to modify this compound into a promising new antibiotic with broad-spectrum activity: NOSO-502. In mouse models, this agent has markedly suppressed drug-resistant bacteria in mice with sepsis, and urinary tract or respiratory infections. Human clinical trials are currently set to begin. There is also some promise that these bacterial compounds are able to neutralize larvae of virus-transmitting mosquitoes (Aedes sp.).
The hope is that investigations and clinical trials using these natural products will jump-start development of new antibiotics, including design and production of hybrid natural products. The researchers are continuing to look for other bacterial natural products that have yet to be discovered.