Microbial natural product drug discovery and development has entered a new era, driven by microbial genomics and synthetic biology. Genome sequencing has revealed the vast potential to produce valuable secondary metabolites in bacteria and fungi. However, many of the biosynthetic gene clusters are silent under standard fermentation conditions. By rational screening for mutations in bacterial ribosomal proteins or RNA polymerases, ribosome engineering is a versatile approach to obtain mutants with improved titers for microbial product formation or new natural products through activating silent biosynthetic gene clusters. In this review, we discuss the mechanism of ribosome engineering and its application to natural product discovery and yield improvement in Streptomyces. Our analysis suggests that ribosome engineering is a rapid and cost-effective approach and could be adapted to speed up the discovery and development of natural product drug leads in the post-genomic era.
Platensimycin (PTM)
is a promising natural product drug lead against
Gram-positive bacteria, including methicillin-resistant Staphylococcus
aureus (MRSA), while the clinical development was hampered
by problems related to its poor solubility and pharmacokinetic properties.
In this study, we used liposomes and micelles as carriers of PTM to
prepare PTM nanoformulations for the treatment of MRSA infection in
mice. PTM-loaded nanoparticles could effectively reduce residual bacteria
in the MRSA-infected macrophage cell model, comparing to free PTM.
More importantly, in vivo studies showed that encapsulation
of PTM by liposomes or micelles effectively improved the pharmacokinetic
properties of PTM in Sprague–Dawley rats and the survival rate
of MRSA-infected C57BL/6J mice. Our study has thus suggested that
the clinically used nanocarriers, such as liposome and micelle, might
also be useful to improve the efficacy of other natural product drug
leads to accelerate their in vivo evaluation and
preclinical development.
The
discovery and clinical use of multitarget monotherapeutic antibiotics
is regarded as a promising approach to reduce the development of antibiotic
resistance. Platencin (PTN), a potent natural antibiotic initially
isolated from a soil actinomycete, targets both FabH and FabF, the
initiation and elongation condensing enzymes for bacterial fatty acid
biosynthesis. However, its further clinical development has been hampered
by poor pharmacokinetics. Herein we report the semisynthesis and biological
evaluation of platencin derivatives 1–15 with potent antibacterial activity against methicillin-resistant Staphylococcus aureus in vitro. Some of these PTN
analogues showed similar yet distinct interactions with FabH and FabF,
as shown by molecular docking, differential scanning fluorometry,
and isothermal titration calorimetry. Compounds 3, 8, 10, and 14 were further evaluated
in a mouse peritonitis model, among which 8 showed in
vivo antibacterial activity comparable to that of PTN. Our results
suggest that semisynthetic modification of PTN is a rapid route to
obtain active PTN derivatives that might be further developed as promising
antibiotics against drug-resistant major pathogens.
A new benzophenone huanglongmycin (HLM) D (1) and two new monomeric xanthones huanglongmycin E (2) and F (3), together with four known aromatic polyketides aloesaponarin II (4) and the previously isolated huanglongmycin A-C (5-7) obtained from cave-derived Streptomyces sp. CB09001. The structures of 1-3 were established based on 1D, 2D NMR and HRMS data. Compounds 1-7 may be biosynthesized by a type II huanglongmycin polyketide synthase based on gene inactivation of hlmG encoding KSɑ in hlm gene cluster and their plausible biosynthetic mechanism was proposed.
Huanglongmycin (HLM) congeners G−N (7−14) were isolated from Streptomyces sp. CB09001. Among them, 10− 12 possesses a tricyclic scaffold with benzene-fused pyran/pyrone, confirmed by X-ray single crystal diffraction analysis of 12. The structure−activity relationship study of 1, 13, and 14 revealed not only the stronger cytotoxicity of 14 against tested cancer cells but also the critical role of the C-7 ethyl group of 14 in its binding to the DNA−topoisomerase I complex.
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