Anthracycline Shunt Metabolites From Philippine Marine Sediment-Derived Streptomyces Destroy Cell Membrane Integrity of Multidrug-Resistant Staphylococcus aureus

Abstract

The rise of antibiotic resistance (ABR) and the drying up of the pipeline for the development of new antibiotics demands an urgent search for new antibiotic leads. While the majority of clinically available antibiotics were discovered from terrestrial Streptomyces, related species from marine sediments as a source of antibiotics remain underexplored. Here, we utilized culture-dependent isolation of thirty-five marine sediment-derived actinobacterial isolates followed by a screening of their antibacterial activity against multidrug-resistant S. aureus ATCC BAA-44. Our results revealed that the crude extract of Streptomyces griseorubens strain DSD069 isolated from marine sediments collected in Romblon, Philippines displays the highest antibacterial activity, with 96.4% growth inhibition. The S. aureus ATCC BAA-44 cells treated with crude extract of Streptomyces griseorubens strain DSD069 showed cell membrane damage as demonstrated by (a) leakage and loss of vital cell constituents, including DNA and proteins, (b) irregular shrinkage of cells, and (c) increase membrane permeability. The antibiotic compounds were identified as Bisanhydroaklavinone and 1-Hydroxybisanhydroaklavinone with MIC value of 6.25 µg/mL and 50.00 µg/mL, respectively. Bisanhydroaklavinone and 1-Hydroxybisanhydroaklavinone are shunt metabolites in the biosynthesis of anticancer anthracycline derivatives namely doxorubicin, daunorubicin, and cinerubins. It is rare, however, that shunt metabolites are accumulated during fermentation of marine sediment-derived Streptomyces strain without genetic modification. Thus, our study provides evidence that natural bacterial strain can produce Bisanhydroaklavinone and 1-Hydroxybisanhydroaklavinone as antibiotic leads to combat ABR.

Marine Sediment-Derived Streptomyces Strain Produces Angucycline Antibiotics against Multidrug-Resistant Staphylococcus aureus Harboring SCCmec Type 1 Gene

“…These anthracyclines shunt metabolites are precursors of anticancer anthracyclines such as doxorubicin, daunorubicin, and cinerubins. They were accumulated in the growth medium during the fermentation of Streptomyces griseorubens strain DSD069, which is a rare event occurring in a non-genetically modified Streptomyces strain [24]. This recent finding shows that Philippine marine sediment-derived actinomycetes are a potentially rich source of new or novel secondary metabolites.…”

“…The sediment samples were air-dried for 8 h in a biosafety hood prior to inoculation in the solid medium of ISP4 (International Streptomyces Project Medium 4) (Difco) with filtered seawater using the dry stamp method (DSM) and heat shock method (HSM) [19,24,46]. The inoculated plates were incubated at room temperature (25 to 28 • C) for 15 to 30 days.…”

“…Pure culture of strain DSD011 was inoculated in Marine Medium 1 (MM1) [19,24] prepared with artificial seawater varying in NaCl concentrations (0%, 3%, 5%, 7%, 10%, 12%, 15%, and 20%) [57]. The plates were incubated at room temperature (25 to 28 • C) for 7 days and checked periodically for the growth of actinomycetes.…”

“…The diversity of marine sediment-derived actinomycetes is indisputable [7,21,22], with decreasing genetic diversity patterns in proportion with depth [13]. This enormous diversity and metabolic changes yield new or novel core structures with potential pharmaceutical applications [23][24][25][26][27][28] as antibacterial [24,27,[29][30][31] and antitumor [32,33] agents. In particular, Salinosporamide A (Marizomib), a novel rare bicyclic beta-lactone gamma-lactam isolated from an obligate marine actinobacterium, Salinispora tropica [34], has been a significant representation of compound derived from marine actinobacteria leading to clinical trials in the treatment of cancer in humans [35,36].…”

“…SCSIO 11791 that produces two new chlorinated bis-indole alkaloid antibiotics namely, dionemycin and 6-OMe-7 ,7"-dichorochromopyrrolic acid [45]. Most recently, our group discovered the antibiotic anthracycline shunt metabolites bisanhydroaklavinone and 1-hydroxybisanhydroaklavinone from a Philippine marine sediment-derived Streptomyces griseorubens strain DSD069, which destroys the cell membrane integrity of multidrug-resistant Staphylococcus aureus [24]. These anthracyclines shunt metabolites are precursors of anticancer anthracyclines such as doxorubicin, daunorubicin, and cinerubins.…”