Dataset Information

Diaza-anthracene Antibiotics from a Freshwater-Derived Actinomycete with Selective Antibacterial Activity toward Mycobacterium tuberculosis.

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.

SUBMITTER: Mullowney MW

PROVIDER: S-EPMC4648258 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Mullowney Michael W MW Hwang Chang Hwa CH Newsome Andrew G AG Wei Xiaomei X Tanouye Urszula U Wan Baojie B Carlson Skylar S Barranis Nanthida Joy NJ hAinmhire EoghainínÓ E Chen Wei-Lun WL Krishnamoorthy Kalyanaraman K White John J Blair Rachel R Lee Hyunwoo H Burdette Joanna E JE Rathod Pradipsinh K PK Parish Tanya T Cho Sanghyun S Franzblau Scott G SG Murphy Brian T BT

ACS infectious diseases 20150311 4

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 ...[more]

PMID: 26594660

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Project description:Tuberculosis is a disease caused primarily by the organism Mycobacterium tuberculosis (Mtb), which claims about 1.5 million lives every year. A challenge that impedes the elimination of this pathogen is the ability of Mtb to remain dormant after primary infection, thus creating a reservoir for the disease in the population that reactivates under more ideal conditions. A better understanding of the physiology of dormant Mtb and therapeutics able to kill these phenotypically tolerant bacilli will be critical for completely eradicating Mtb. Our groups are focusing on characterizing the activity of derivatives of the marine natural product (+)-puupehenone (1). Recently, the Rohde group reported that puupehedione (2) and 15-α-methoxypuupehenol (3) exhibit enhanced activity in an in vitro multi-stress dormancy model of Mtb. To optimize the antimycobacterial activity of these terpenoids, novel 15-α-methoxy- and 15-α-acetoxy-puupehenol esters were prepared from (+)-puupehenone (1) accessed through a (+)-sclareolide-derived β-hydroxyl aldehyde. For added diversity, various congeners related to (1) were also prepared from a common borono-sclareolide donor, which resulted in the synthesis of epi-puupehenol and the natural products (+)-chromazonarol and (+)-yahazunol. In total, we generated a library of 24 compounds, of which 14 were found to be active against Mtb, and the most active compounds retained the enhanced activity against dormant Mtb seen in the parent compound. Several of the 15-α-methoxy- and 15-α-acetoxy-puupehenol esters possessed potent activity against actively dividing and dormant Mtb. Intriguingly, the closely related triisobutyl derivative 16 showed similar activity to 1 in actively dividing Mtb but lost about 178-fold activity against dormant Mtb. However, the monopivaloyl compound 13 showed a modest 3- to 4-fold loss in activity in both actively dividing and dormant Mtb relative to the activity of 1 revealing the importance of the free OH at C19 supporting the potential role of quinone methide formation as critical for activity in dormant Mtb. Elucidating important structure-activity relationships and the mechanism of action of this natural product-inspired chemical series may yield insights into vulnerable drug targets in dormant bacilli and new therapeutics to more effectively target dormant Mtb.

Dataset Information

Diaza-anthracene Antibiotics from a Freshwater-Derived Actinomycete with Selective Antibacterial Activity toward Mycobacterium tuberculosis.

Publications

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

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