Abstract
Multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis are resistant to first- and second-line drug regimens and resulted in 210,000 fatalities in 2013. In the current study, we screened a library of aquatic bacterial natural product fractions for their ability to inhibit this pathogen. A fraction from a Lake Michigan bacterium exhibited significant inhibitory activity, from which we characterized novel diazaquinomycins H and J. This antibiotic class displayed an in vitro activity profile similar or superior to clinically used anti-tuberculosis agents and maintained this potency against a panel of drug-resistant M. tuberculosis strains. Importantly, these are among the only freshwater-derived actinomycete bacterial metabolites described to date. Further in vitro profiling against a broad panel of bacteria indicated that this antibiotic class selectively targets M. tuberculosis. Additionally, in the case of this pathogen we present evidence counter to previous reports that claim the diazaquinomycins target thymidylate synthase in Gram-positive bacteria. Thus, we establish freshwater environments as potential sources for novel antibiotic leads and present the diazaquinomycins as potent and selective inhibitors of M. tuberculosis.
Highlights
Multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis are resistant to first- and second-line drug regimens and resulted in 210,000 fatalities in 2013
Further in vitro profiling against a broad panel of bacteria indicated that this antibiotic class selectively targets M. tuberculosis
A preliminary in vitro growth inhibition screening of this fraction library against M. tuberculosis H37Rv led to the identification of a Micromonospora sp. isolated from Lake Michigan sediment, whose fraction exhibited submicromolar inhibitory activity
Summary
Keywords natural products; Great Lakes; actinobacteria; antibiotic; diazaquinomycin; drug discovery. Libraries of organisms (including bacteria) and their resulting secondary metabolites were created that were not incorporated in the biological screening efforts of previous decades.[6,7] This investment had a considerable effect toward progress in natural product drug discovery, affording the development of several drugs from marine sources (Prialt, Yondelis, Halaven).[8,9,10]. Isolated from Lake Michigan sediment, whose fraction exhibited submicromolar inhibitory activity From this strain we isolated and characterized two novel secondary metabolites, diazaquinomycins H and J (DAQH and DAQJ), which to our knowledge are among the only freshwater-derived actinomycete metabolites described to date.[12,13] Further in vitro profiling suggested that this group of diaza-anthracene antibiotics selectively targets M. tuberculosis over other bacteria and is active against several forms of drug-resistant TB. We present the identification and in vitro biological characterization of this unique antibiotic class
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
