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.
journal_name
ACS Infect Disjournal_title
ACS infectious diseasesauthors
Mullowney MW,Hwang CH,Newsome AG,Wei X,Tanouye U,Wan B,Carlson S,Barranis NJ,hAinmhire E,Chen WL,Krishnamoorthy K,White J,Blair R,Lee H,Burdette JE,Rathod PK,Parish T,Cho S,Franzblau SG,Murphy BTdoi
10.1021/acsinfecdis.5b00005subject
Has Abstractpub_date
2015-04-10 00:00:00pages
168-174issue
4issn
2373-8227journal_volume
1pub_type
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