Amycomicin is a potent and specific antibiotic discovered with a targeted interaction screen

Abstract

The rapid emergence of antibiotic-resistant pathogenic bacteria has accelerated the search for new antibiotics. Many clinically used antibacterials were discovered through culturing a single microbial species under nutrient-rich conditions, but in the environment, bacteria constantly encounter poor nutrient conditions and interact with neighboring microbial species. In an effort to recapitulate this environment, we generated a nine-strain actinomycete community and used 16S rDNA sequencing to deconvolute the stochastic production of antimicrobial activity that was not observed from any of the axenic cultures. We subsequently simplified the community to just two strains and identified sp. AA4 as the producing strain and M145 as an inducing strain. Bioassay-guided isolation identified amycomicin (AMY), a highly modified fatty acid containing an epoxide isonitrile warhead as a potent and specific inhibitor of Amycomicin targets an essential enzyme (FabH) in fatty acid biosynthesis and reduces infection in a mouse skin-infection model. The discovery of AMY demonstrates the utility of screening complex communities against specific targets to discover small-molecule antibiotics.

Inducible Antibacterial Activity in the Bacillales by Triphenyl Tetrazolium Chloride

“…Various reports support the role of the chemical environment surrounding bacteria as a trigger of metabolic responses, with the term OSMAC illustrating how the metabolic output of a strain can be finely tuned or stimulated in the presence of natural or synthetic signals [22][23][24] . Some of the most recently reported novel bioactive substances have been isolated either from a chemical interaction with a neighboring microbial strain or natural signal 25 or by enrichment cultivation methods which concentrate the chemical ecological signals and allow the growth of otherwise non-cultivatable bacteria 21,38 . Tetrazolium salts, particularly the widely used compound TTC, have not been reported as inducers of antimicrobial behavior, and thus this study reveals a novel platform of induction of bioactive substances in microbial strains.…”

Biosynthetic Routes to Natural Isocyanides

“…Aerocyanidin antibiotic ( 13 ) was isolated in the 1980s and was followed by a few other close congeners including amycomycin ( 14 ) . The biosynthetic origin especially concerning the origin of the isocyanide is currently unknown.…”

“…Epoxy‐isocyanides such as amycomicin ( 14 ) are known to be particularly unstable under acidic or mildly basic conditions. They are observed to evolve spontaneously to keto‐epoxy counterparts (such as 33 ) by a Payne rearrangement leading to the nucleofuge departure of the isocyanide function (Scheme ) , …”

Identification and Testing of Antidermatophytic Oxaborole-6-Benzene Sulphonamide Derivative (OXBS) from Streptomyces atrovirens KM192347 Isolated from Soil

“…Aliquots of starch nitrate broth (250 mL for each) in 500 mL Erlenmeyer flasks (Gomhuria, Cairo, Egypt) were inoculated by (1% v/v) spore suspensions of actively growing cells in the mid-log phase after four days of growth of the S. atrovirens strain. The inoculated samples were incubated at different agitation rates (0, 50, 100, 150, 200, and 250 rpm) for different times (3-14 days), at different incubation temperatures (15,20,25,30,35,40,45, and 50 • C) and different pH values (4)(5)(6)(7)(8)(9)(10)(11)(12). Then CFCS were prepared by centrifuging the culture (5000Xg for 10 min at 4 • C).…”

“…Prior to this period, antifungal chemotherapy included only two kinds of compounds-potassium iodide, which was effective in the treatment of sporotrochosis, and two useful polyenes, nystatin and amphotericin B, which were introduced in the1950s. Except for the development of flucytosine (1964), there was a little progress until the development of azole drugs in the early 1970s [9][10][11][12][13][14]. Therefore, only a limited number of antifungal agents, such as polyenes and azoles, are currently available for the treatment of life-threatening fungal infection.…”