Diaza-anthracene Antibiotics from a Freshwater-Derived Actinomycete with Selective Antibacterial Activity toward <i>Mycobacterium tuberculosis</i>

Abstract

Multidrug- and extensively drug-resistant strains of <i>Mycobacterium tuberculosis</i> 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 <i>M. tuberculosis</i> 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 <i>M. tuberculosis</i>. 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 <i>M. tuberculosis</i>.