The bleomycins (BLMs) are important clinical drugs extensively used in combination chemotherapy for the treatment of various cancers. Dose-dependent lung toxicity and the development of drug resistance have restricted their wide applications. 6'-Deoxy-BLM Z, a recently engineered BLM analogue with improved antitumor activity, has the potential to be developed into the next-generation BLM anticancer drug. However, its low titer in the recombinant strain Streptomyces flavoviridis SB9026 has hampered current efforts, which require sufficient compound, to pursue preclinical studies and subsequent clinical development. Here, we report the strain improvement by combined UV mutagenesis and ribosome engineering, as well as the fermentation optimization, for enhanced 6'-deoxy-BLM production. A high producer, named S. flavoviridis G-4F12, was successfully isolated, producing 6'-deoxy-BLM at above 70 mg/L under the optimized fermentation conditions, representing a sevenfold increase in comparison with that of the original producer. These findings demonstrated the effectiveness of combined empirical breeding methods in strain improvement and set the stage for sustainable production of 6'-deoxy-BLM via pilot-scale microbial fermentation.
The bleomycins (BLMs) belong to a subfamily of glycopeptide antibiotics and are clinically applied in combination chemotherapy regimens to treat various malignancies. But the therapeutic applications of BLMs are restricted by the accompanied dose-dependent lung toxicity and potential incidence of lung fibrosis. Many efforts have been devoted to develop novel BLM analogues, for seeking of drug leads with improved antitumor activity and/or reduced lung toxicity. The progresses in the biosynthetic studies of BLMs have greatly expedited the process to achieve such goals. This review highlights the discovery and development of microbial BLM analogues in the past two decades, especially those derived from engineered biosynthesis. Moreover, the summarized structure-activity relationship, which is specifically focusing on the sugar moiety, shall shed new insights into the prospective development of BLM analogues.
β-rubromycin (β-RUB) ( 1) is an efficient inhibitor of human telomerase possessing a unique spiroketal moiety as a potential pharmacophore and regarded as a promising anticancer drug lead. But the development of (β-RUB) (1) has long been hampered
The
cationic glycopeptide bleomycin (BLM) is a broad-spectrum chemotherapy
drug clinically applied to treat various malignant tumors. The poor
cell membrane permeability of BLM, which is prone to high dose usage
and may consequently induce dose-dependent lung toxicity, is a sticking
point to limit clinical applications of BLM. As a commercial biosurfactant,
the anionic lipopeptide surfactin (SF) is well known for its potent
ability to disturb membranes and widely applied in cosmetic area as
a permeabilization synergist. In this work, our in vitro investigations showed that SF could ameliorate the cell internalization
of BLM, and the combined usage of SF notably improved the antitumor
activity of BLM or its analogues while having no obvious effects on
normal cells. Subsequent in vivo assessments on the
subcutaneous treatment of A375 melanoma in mice demonstrated that
SF could also enhance the therapeutic effects of BLM family compounds
in subeffective doses, with no obvious toxicities on lungs and skin.
Also, our preliminary results suggested the formation of complex micelles
at the nanoscale by the self-assembly of BLM and SF, which may contribute
to the ameliorated internalization and the antitumor effect of BLM.
Therefore, SF could be applied as a potential synergist for BLM to
reduce its treatment dose while maintaining the therapeutic effect
on treatment of skin carcinoma, which provides us an alternative way
to minimize the side effects of clinical BLM and facilitate the development
of new BLM-type drugs.
Objectives
The rapid development of drug-resistant bacteria, especially MRSA, poses severe threats to global public health. Adoption of antibiotic adjuvants has proved to be one of the efficient ways to solve such a crisis. Platensimycin and surfactin were comprehensively studied to combat prevalent MRSA skin infection.
Methods
MICs of platensimycin, surfactin or their combinations were determined by resazurin assay, while the corresponding MBCs were determined by chequerboard assay. Growth inhibition curves and biofilm inhibition were determined by OD measurements. Membrane permeability analysis was conducted by propidium iodide staining, and morphological characterizations were performed by scanning electron microscopy. Finally, the therapeutic effects on MRSA skin infections were evaluated in scald-model mice.
Results
The in vitro assays indicated that surfactin could significantly improve the antibacterial performance of platensimycin against MRSA, especially the bactericidal activity. Subsequent mechanistic studies revealed that surfactin not only interfered with the biofilm formation of MRSA, but also disturbed their cell membranes to enhance membrane permeability, and therefore synergistically ameliorated MRSA cellular uptake of platensimycin. Further in vivo assessment validated the synergistic effect of surfactin on platensimycin and the resultant enhancement of therapeutical efficacy in MRSA skin-infected mice.
Conclusions
The combination of effective and biosafe surfactin and platensimycin could be a promising and efficient treatment for MRSA skin infection, which could provide a feasible solution to combat the major global health threats caused by MRSA.
A Tripterygium wilfordii endophyte, Streptomyces sp. CB04723, was shown to produce an unusually
highly reduced cytotoxic
cinnamoyl lipid, tripmycin A (1). Structure–activity
relationship studies revealed that both the cinnamyl moiety and the
saturated fatty acid side chain are indispensable to the over 400-fold
cytotoxicity improvement of 1 against the triple-negative
breast cancer cell line MDA-MB-231 compared to 5-(2-methylphenyl)-4-pentenoic
acid (2). Bioinformatical analysis, gene inactivation,
and overexpression revealed that Hxs15 most likely acted as an enoyl
reductase and was involved with the side chain reduction of 1, which provides a new insight into the biosynthesis of cinnamoyl
lipids.
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