Antibacterial properties and clinical potential of pleuromutilins

Goethe, Olivia; Heuer, Abigail M.; Ma, Xiaoshen; Wang, Zhixun; Herzon, Seth B.

doi:10.1039/c8np00042e

Cited by 72 publications

(61 citation statements)

References 146 publications

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“…One other major limitation regarding the general application of this approach is that the microbes must be susceptible to these initiation complex inhibitors. Retapamulin is a member of the pleuromutilin class of antibiotics that show activity against a broad spectrum of grampositive bacteria, though some derivatives show activity against gram-negative bacteria as well (50,51). To increase susceptibility to retapamulin, the group of Vázquez-Laslop and Mankin (35) used a tolC mutant strain of E. coli, an approach that may need to be employed in other bacteria.…”

Section: Discussionmentioning

confidence: 99%

Identifying small proteins by ribosome profiling with stalled initiation complexes

Weaver¹,

Mohammad

Buskirk

et al. 2019

Preprint

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Section: Discussionmentioning

confidence: 99%

Identifying small proteins by ribosome profiling with stalled initiation complexes

Weaver¹,

Mohammad

Buskirk

et al. 2019

Preprint

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“…One other major limitation regarding the general application of this approach is that the microbes must be susceptible to these initiation complex inhibitors. Retapamulin is a member of the pleuromutilin class of antibiotics that show activity against a broad spectrum of Gram-positive bacteria, though some derivatives show activity against Gram-negative bacteria as well (54,55). To increase susceptibility to retapamulin, the group of Vázquez-Laslop and Mankin (37) used a tolC mutant strain of E. coli, an approach that may need to be employed in other bacteria.…”

Section: Fig 7 Legend (Continued)mentioning

confidence: 99%

Identifying Small Proteins by Ribosome Profiling with Stalled Initiation Complexes

Weaver

Mohammad

Buskirk

et al. 2019

mBio

156

240

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Small proteins consisting of 50 or fewer amino acids have been identified as regulators of larger proteins in bacteria and eukaryotes. Despite the importance of these molecules, the total number of small proteins remains unknown because conventional annotation pipelines usually exclude small open reading frames (smORFs). We previously identified several dozen small proteins in the model organism Escherichia coli using theoretical bioinformatic approaches based on sequence conservation and matches to canonical ribosome binding sites. Here, we present an empirical approach for discovering new proteins, taking advantage of recent advances in ribosome profiling in which antibiotics are used to trap newly initiated 70S ribosomes at start codons. This approach led to the identification of many novel initiation sites in intergenic regions in E. coli. We tagged 41 smORFs on the chromosome and detected protein synthesis for all but three. Not only are the corresponding genes intergenic but they are also found antisense to other genes, in operons, and overlapping other open reading frames (ORFs), some impacting the translation of larger downstream genes. These results demonstrate the utility of this method for identifying new genes, regardless of their genomic context. IMPORTANCE Proteins comprised of 50 or fewer amino acids have been shown to interact with and modulate the functions of larger proteins in a range of organisms. Despite the possible importance of small proteins, the true prevalence and capabilities of these regulators remain unknown as the small size of the proteins places serious limitations on their identification, purification, and characterization. Here, we present a ribosome profiling approach with stalled initiation complexes that led to the identification of 38 new small proteins.

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“…In addition, the ability to overproduce valuable NPs enables access to the natural scaffold that can be further modified semisynthetically to optimize biological activity. For example, several pleuromutilin derivatives are under clinical development as systemic antibiotics [37], and nowheterologous expression of selected late stage biosynthetic enzymes in A. oryzae provides a platform for the bioconversion of modified precursors into semisynthetic pleuromutilin derivatives with improved antibiotic activity [38]. Figure 2.…”

Section: Pathway Engineeringmentioning

confidence: 99%

Strategies for Engineering Natural Product Biosynthesis in Fungi

Skellam

2019

Trends in Biotechnology

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Fungi are a prolific source of bioactive compounds, some of which have been developed as essential medicines and life-enhancing drugs. Genome sequencing has revealed that fungi have the potential to produce considerably more natural products (NPs) than are typically observed in the laboratory. Recently, there have been significant advances in the identification, understanding, and engineering of fungal biosynthetic gene clusters (BGCs). This review briefly describes examples of the engineering of fungal NP biosynthesis at the global, pathway, and enzyme level using in vivo and in vitro approaches and refers to the range and scale of heterologous expression systems available, developments in combinatorial biosynthesis, progress in understanding how fungal BGCs are regulated, and the applications of these novel biosynthetic enzymes as biocatalysts. Fungal NPs and Human Health NPs (see Glossary) or NP derivatives represented 25% of all FDA-approved drugs in the years spanning 1981 to 2014 [1]. Fungi are prolific producers of some of these important drugs, such as antibiotics (e.g., penicillin, pleuromutilin), cholesterol-lowering drugs (e.g., lovastatin, compactin), and immunosuppressants (e.g., mycophenolic acid, cyclosporine). Fungal NPs have many biological activities, ranging from carcinogens (e.g., aflatoxins), deadly toxins (e.g., a-amanitin), and industrial fungicides (e.g., strobilurin) to food colorants (e.g., azaphilones), hormones (e.g., gibberellin), and psychedelics (e.g., psilocybin) [2,3]. In nature, these NPs serve to protect fungi from predators (e.g., insects), UV radiation, and competition from other microorganisms and have evolved to secure their survival in niche habitats; they just happen to have had a profound effect on human health. The broad spectrum of biological activities reflects their structural diversity, which arises from their biosynthetic classification (e.g., polyketides, peptides, terpenes, alkaloids) (Figure 1). The complexity of fungal secondary metabolism presents numerous challenges for traditional drug discovery. Fungi often produce NPs at very low levels or in response to specific environmental cues that are difficult to reproduce in the laboratory [4]. The prominence of NPs in the pharmaceutical industry and re-emerging interest in NPs as lead structures in drug discovery [5] require methods to engineer improved NP analogs and activate silent biosynthetic pathways. In recent years there have been substantial advances in strategies for engineering fungal NP biosynthesis (Figure 2, Key Figure), which are highlighted in this review. These strategies can be divided into three broad categories: (i) inducing global transcriptional perturbations (e.g., through epigenetic modifications or the overexpression of global transcriptional regulators), which effectively 'awakens' the biosynthetic machinery and often affects multiple pathways resulting in the production of a variety of NPs, but is unpredictable and difficult to control Highlights

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Antibacterial properties and clinical potential of pleuromutilins

Cited by 72 publications

References 146 publications

Identifying small proteins by ribosome profiling with stalled initiation complexes

Identifying small proteins by ribosome profiling with stalled initiation complexes

Identifying Small Proteins by Ribosome Profiling with Stalled Initiation Complexes

Strategies for Engineering Natural Product Biosynthesis in Fungi

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