Oxytetracycline Biosynthesis

Pickens, Lauren B.; Tang, Yi

doi:10.1074/jbc.r110.130419

Cited by 91 publications

(99 citation statements)

References 82 publications

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“…2). The TcmN-like cyclase participates in first-and second-ring cyclizations (27)(28)(29), whereas TcmI-, OxyN-, and TcmJ-like cyclases are thought to direct subsequent ring closures (5,30). All four of these categories share an evolutionary history with their clustered KS (Fig.…”

Section: Resultsmentioning

confidence: 99%

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Hillenmeyer

Vandova

Berlew

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Natural product biosynthetic pathways generate molecules of enormous structural complexity and exquisitely tuned biological activities. Studies of natural products have led to the discovery of many pharmaceutical agents, particularly antibiotics. Attempts to harness the catalytic prowess of biosynthetic enzyme systems, for both compound discovery and engineering, have been limited by a poor understanding of the evolution of the underlying gene clusters. We developed an approach to study the evolution of biosynthetic genes on a cluster-wide scale, integrating pairwise gene coevolution information with large-scale phylogenetic analysis. We used this method to infer the evolution of type II polyketide gene clusters, tracing the path of evolution from the single ancestor to those gene clusters surviving today. We identified 10 key gene types in these clusters, most of which were swapped in from existing cellular processes and subsequently specialized. The ancestral type II polyketide gene cluster likely comprised a core set of five genes, a roster that expanded and contracted throughout evolution. A key C24 ancestor diversified into major classes of longer and shorter chain length systems, from which a C20 ancestor gave rise to the majority of characterized type II polyketide antibiotics. Our findings reveal that (i) type II polyketide structure is predictable from its gene roster, (ii) only certain gene combinations are compatible, and (iii) gene swaps were likely a key to evolution of chemical diversity. The lessons learned about how natural selection drives polyketide chemical innovation can be applied to the rational design and guided discovery of chemicals with desired structures and properties.evolution | polyketide | natural products | gene cluster

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Section: Resultsmentioning

confidence: 99%

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Hillenmeyer

Vandova

Berlew

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This gene is apparently regulated by a MarR-family transcriptional regulator, OxyTA1 (also known as OtrR) that might also respond to oxytetracycline (Fig. 4) (Petkovic et al, 2006;Perera and Grove, 2010; Pickens and Tang, 2010). While the proposed mechanism requires further investigation, this mode of regulation offers potential advantages for cells.…”

Section: Oxytetracyclinementioning

confidence: 99%

The expression of antibiotic resistance genes in antibiotic‐producing bacteria

Mak

Nodwell

2014

Molecular Microbiology

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SummaryAntibiotic-producing bacteria encode antibiotic resistance genes that protect them from the biologically active molecules that they produce. The expression of these genes needs to occur in a timely manner: either in advance of or concomitantly with biosynthesis. It appears that there have been at least two general solutions to this problem. In many cases, the expression of resistance genes is tightly linked to that of antibiotic biosynthetic genes. In others, the resistance genes can be induced by their cognate antibiotics or by intermediate molecules from their biosynthetic pathways. The regulatory mechanisms that couple resistance to antibiotic biosynthesis are mechanistically diverse and potentially relevant to the origins of clinical antibiotic resistance.

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“…The role of the acyl-CoA-ligase SsfL2, homologous to OxyH from the oxy gene cluster, putatively involved in the formation of the fourth ring of the TC-like compound SF2527 was discussed by Pickens et al (71). Interestingly, the OxyH was demonstrated by gene-inactivation studies to be dispensable: therefore, its function is not yet understood (4). Considering that the cyclisation steps in TC biosynthesis occur between enzymatically catalysed reactions and spontaneous chemically-driven reactions, it is not surprising that the mechanism of cyclisation is not yet fully understood.…”

Section: Formation Of the Tetracycline Backbone In Otc Biosynthesismentioning

confidence: 99%

“…The lower peripheral region, which extends from C10 to C4a, is involved in the interaction with the 30S ribosomal subunit via the oxygen functional groups on carbon atoms C10--C1, and the C2 amide functionality (2). It has been demonstrated that most modifi cations along the lower peripheral region of TC greatly decrease antimicrobial activity, whereas derivatives modifi ed along the upper peripheral region, particularly on positions C7-C9, have demonstrated greater activity against many diff erent biological targets (2,4).…”

Section: Introductionmentioning

confidence: 99%

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Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics

Petković

Lukežič²,

Šušković

2017

Food Technol. Biotechnol.

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SummaryNatural tetracycline (TC) antibiotics were the fi rst major class of therapeutics to earn the distinction of 'broad-spectrum antibiotics' and they have been used since the 1940s against a wide range of both Gram-positive and Gram-negative pathogens, mycoplasmas, intracellular chlamydiae, rickett siae and protozoan parasites. The second generation of semisynthetic tetracyclines, such as minocycline and doxycycline, with improved antimicrobial potency, were introduced during the 1960s. Despite emerging resistance to TCs erupting during the 1980s, it was not until 2006, more than four decades later, that a third--generation TC, named tigecycline, was launched. In addition, two TC analogues, omadacycline and eravacycline, developed via (semi)synthetic and fully synthetic routes, respectively, are at present under clinical evaluation. Interestingly, despite very productive early work on the isolation of a Streptomyces aureofaciens mutant strain that produced 6-demethyl-7-chlortetracycline, the key intermediate in the production of second-and third-generation TCs, biosynthetic approaches in TC development have not been productive for more than 50 years. Relatively slow and tedious molecular biology approaches for the genetic manipulation of TC-producing actinobacteria, as well as an insuffi cient understanding of the enzymatic mechanisms involved in TC biosynthesis have signifi cantly contributed to the low success of such biosynthetic engineering eff orts. However, new opportunities in TC drug development have arisen thanks to a signifi cant progress in the development of aff ordable and versatile biosynthetic engineering and synthetic biology approaches, and, importantly, to a much deeper understanding of TC biosynthesis, mostly gained over the last two decades.

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Oxytetracycline Biosynthesis

Cited by 91 publications

References 82 publications

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

The expression of antibiotic resistance genes in antibiotic‐producing bacteria

Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics

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