Antibiotics from Aquatic-Derived Actinomycete Bacteria that Inhibit M. tuberculosis
thesisposted on 17.02.2017, 00:00 by Michael Warren Mullowney
The World Health Organization (WHO) estimated that 1.5 million deaths were attributed to TB infection in 2014. Of these, 190,000 fatalities were a result of multidrug- and extensively drug-resistant strains of M. tuberculosis. Fortunately, natural products have proven essential as components of drug discovery, serving as both a direct source of small molecule therapies and as an inspiration for biologically active synthetic derivatives. In the studies detailed herein, a library of natural product fractions from aquatic-derived actinomycete bacteria were screened for their ability to inhibit M. tuberculosis. Fractions from both marine- and fresh water-derived actinomycetes exhibited significant inhibitory activity, from which known and novel antibiotics were characterized. These included novel analogs of the diazaquinomycin class of antibiotics, two of which are among the first novel secondary metabolites isolated from freshwater-derived actinomycetes. This class exhibited potent and selective inhibition of M. tuberculosis with a mechanism of action involving high levels of oxidative stress. Additionally, further separation of an active fraction from a strain collected in the East Sea of Vietnam resulted in the discovery of a novel pimarane diterpene and the isolation of a series of angucycline antibiotics. This diterpene represents one of approximately twenty actinomycete-produced diterpenes reported to date. Overall, these studies highlight collaborative efforts to discover novel anti-tuberculosis drug-leads from unique marine locations and the underexplored freshwater environment.