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Abstract
BackgroundThe deep-sea-derived microbe Streptomyces koyangensis SCSIO 5802 produces neoabyssomicins A–B (1–2) and abyssomicins 2 (3) and 4 (4). Neoabyssomicin A (1) augments human immunodeficiency virus-1 (HIV-1) replication whereas abyssomicin 2 (3) selectively reactivates latent HIV and is also active against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA). Structurally, neoabyssomicins A–B constitute a new subtype within the abyssomicin family and feature unique structural traits characteristic of extremely interesting biosynthetic transformations.ResultsIn this work, the biosynthetic gene cluster (BGC) for the neoabyssomicins and abyssomicins, composed of 28 opening reading frames, was identified in S. koyangensis SCSIO 5802, and its role in neoabyssomicin/abyssomicin biosynthesis was confirmed via gene inactivation and heterologous expression experiments. Bioinformatics and genomics analyses enabled us to propose a biosynthetic pathway for neoabyssomicin/abyssomicin biosynthesis. Similarly, a protective export system by which both types of compounds are secreted from the S. koyangensis producer was identified, as was a four-component ABC transporter-based import system central to neoabyssomicin/abyssomicin biosynthesis. Furthermore, two regulatory genes, abmI and abmH, were unambiguously shown to be positive regulators of neoabyssomicin/abyssomicin biosynthesis. Consistent with their roles as positive regulatory genes, the overexpression of abmI and abmH (independent of each other) was shown to improve neoabyssomicin/abyssomicin titers.ConclusionsThese studies provide new insight into the biosynthesis of the abyssomicin class of natural products, and highlight important exploitable features of its BGC for future efforts. Elucidation of the neoabyssomicin/abyssomicin BGC now enables combinatorial biosynthetic initiatives aimed at improving both the titers and pharmaceutical properties of these important natural products-based drug leads.
Highlights
The deep-sea-derived microbe Streptomyces koyangensis SCSIO 5802 produces neoabyssomicins A–B (1–2) and abyssomicins 2 (3) and 4 (4)
The genes associated with biosynthetic Diels–Alder chemistry, oxygenation, as well as genes having to do with transport and regulatory functions, were found in the abm biosynthetic gene cluster (BGC) and showed homologies to corresponding counterparts in the atropabyssomicin C pathway (Table 1)
Disruption of abmI and abmH completely abolished neoabyssomicin/abyssomicin production (Fig. 6a, traces ii, iii). These results demonstrated that abmI and abmH are both pivotal positive regulators of neoabyssomicin/abyssomicin biosynthesis
Summary
The deep-sea-derived microbe Streptomyces koyangensis SCSIO 5802 produces neoabyssomicins A–B (1–2) and abyssomicins 2 (3) and 4 (4). Infectious diseases constitute a leading cause of death worldwide and continue to advance in their lethality as drug resistance becomes more widespread This concern, coupled with revelations about as yet, untapped sources of molecular diversity, has spurred intense efforts to discover new drug candidates with novel structures/modes of action able to circumvent or ablate bacterial mechanisms of drug resistance. Within this context, three novel natural products, abyssomicin C (Fig. 1) and its analogues abyssomicins B and D, were discovered from the marine actinomycete strain Verrucosispora sp. Type II family members are “enantiomeric” counterparts of the type I family compounds and are further grouped into two subtypes (type IIA and type IIB) based on difference in C-4 methyl substitution (see Fig. 1 for the chemical structures of the representative for each type/subtype)
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