Discovery of antibiotics from anaerobic gut microbiome bacteria

Allie Morgan Bradley

doi:10.17918/00011513

Antibiotic resistance is on the rise, and with the lack of antibiotic discovery, a major health crisis on foreseeable. Indeed, it is estimated that in 2050, 8.22 million deaths will be associated with antimicrobial resistance, with multidrug-resistant ESKAPE pathogens majorly contributing to these deaths. More than 75% of antibiotics are natural products isolated from plants, fungi, and bacteria. Most antibiotics have an original source in aerobic bacteria, whereas anaerobic bacteria as a source for new antibiotics have been largely overlooked. Recent genome mining of genomes of anaerobic bacteria, the oldest terrestrial life forms, identified many biosynthetic gene clusters (BGCs) with potential for antibiotic production. The human gut microbiome is a large niche for anaerobic bacteria, and we propose that this is a rich untapped source of biosynthetic diversity. Antibiotics from the gut microbiome have already been found, such as colibactin from E. coli Nissle 1917 and Nisin from Lactococcus lactis. We set out to screen 13 anaerobic gut microbiome bacteria for their ability to produce antibiotic molecules. We found that an extract of anaerobe Yersinia enterocolitica WA-314 antagonizes Staphylococcus aureus USA300 and Pseudomonas aeruginosa PAO1G, as determined by inhibition assays. In parallel, anaerobe Parabacteroides distasonis HM-169 extract antagonizes Staphylococcus aureus USA300, as determined by inhibition assays. Purification of this molecule from a 6 L culture has helped characterize it, with a retention time of ~2 minutes and a mass-to-charge ratio of 321.1306 m/z. Liquid chromatography-mass spectrometry has shown it is not ciprofloxacin, nystatin, polymyxin B, or vancomycin. The identification of antibiotic molecules produced by Yersinia enterocolitica and Parabacteroides distasonis has shown that anaerobic gut microbiome bacteria remain a rich resource for new antibiotic discovery to combat the rising antimicrobial resistance crisis. Within the set of anaerobes screened here for antibiotic activity, we found a BGC for an aryl polyene cluster in A. finegoldii. Aryl polyenes are a unique class of molecules that hypothetically can be antibiotics. A 7th class of aryl polyene is characterized, and the function of the molecule has been tested. The 7th class of aryl polyene is proposed to be called APEAf and is produced by Alistipes finegoldii DSM 17242, an anaerobic gut microbiome commensal. The BGC encoding the aryl polyene shows similarities and differences with the BGCs of flexirubin, xanthomonadin, and E. coli APE. It is very likely that the molecule contains an aryl ring bearing a methyl group and a polyene tail with 7 repeats. It has a mass of 348.1580 Da. While E. coli APE is biosynthesized from a hydroxybenzoic acid, APEAf is proposed to be synthesized from tyrosine, as in flexirubin. Antifungal and antibiotic inhibition assays were performed with the APEAf extract, and no culture inhibition was observed. The identification of APEAf from Alistipes finegoldii shows that aryl polyenes are a large class of molecules that are continuing to be found across different environments.

Discovery of antibiotics from anaerobic gut microbiome bacteria

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Discovery of antibiotics from anaerobic gut microbiome bacteria

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