Antibacterial sulfur-containing platensimycin and platencin congeners from Streptomyces platensis SB12029

Dong, Liao-Bin; Rudolf, Jeffrey D.; Shen, Ben

doi:10.1016/j.bmc.2016.04.026

Cited by 25 publications

(51 citation statements)

References 26 publications

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“…We recently discovered two new sulfur-containing congeners of PTM from an engineered dual PTM-PTN overproducing strain S. platensis SB12029 (see Section 3.3) (Figure 3) [31]. We first identified the sulfur-containing pseudodimer PTM D1 ( 29 ), a likely nonenzymatic product due to a heteroatom Michael addition of a sulfur atom attacking the enone, which lead to the identification of its presumptive prescursor PTM S1, a thioacid analogue of PTM ( 11 ).…”

Section: Discovery Of Ptm and Ptnmentioning

confidence: 99%

“…We first identified the sulfur-containing pseudodimer PTM D1 ( 29 ), a likely nonenzymatic product due to a heteroatom Michael addition of a sulfur atom attacking the enone, which lead to the identification of its presumptive prescursor PTM S1, a thioacid analogue of PTM ( 11 ). While PTM S1 was intrinsically unstable and prevented us from directly determining its antibacterial activity, PTM D1 (MIC = 0.5 µg mL −1 ) was found to retain the strong antibacterial activity of PTM (Table 1) [31]. It is still unclear how the pseudodimer exerts its activity.…”

Section: Discovery Of Ptm and Ptnmentioning

confidence: 99%

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Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

Rudolf

Dong

Shen

2017

Biochemical Pharmacology

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Natural products have served as the main source of drugs and drug leads, and natural products produced by microorganisms are one of the most prevalent sources of clinical antibiotics. Their unparalleled structural and chemical diversities provide a basis to investigate fundamental biological processes while providing access to a tremendous amount of chemical space. There is a pressing need for novel antibiotics with new mode of actions to combat the growing challenge of multidrug resistant pathogens. This review begins with the pioneering discovery and biological activities of platensimycin (PTM) and platencin (PTN), two antibacterial natural products isolated from Streptomyces platensis. The elucidation of their unique biochemical mode of action, structure-activity relationships, and pharmacokinetics is presented to highlight key aspects of their biological activities. It then presents an overview of how microbial genomics has impacted the field of PTM and PTN and revealed paradigm-shifting discoveries in terpenoid biosynthesis, fatty acid metabolism, and antibiotic and antidiabetic therapies. It concludes with a discussion covering the future perspectives of PTM and PTN in regard to natural products discovery, bacterial diterpenoid biosynthesis, and the pharmaceutical promise of PTM and PTN as antibiotics and for the treatment of metabolic disorders. PTM and PTN have inspired new discoveries in chemistry, biology, enzymology, and medicine and will undoubtedly continue to do so.

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Section: Discovery Of Ptm and Ptnmentioning

confidence: 99%

Section: Discovery Of Ptm and Ptnmentioning

confidence: 99%

Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

Rudolf

Dong

Shen

2017

Biochemical Pharmacology

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“…We found ourselves in an excellent position to contribute towards the design and development of PTM and PTN analogues given our construction of the PTM-PTN dual overproducing strain Streptomyces platensis SB12029 17 and its success in revealing new natural products 18 and providing new opportunities for combinatorial biosynthesis. 19,20 While total synthetic routes of both PTM and PTN are available, 26,27 titers of PTM from fermentation of SB12029 are >300 mg L −1,17,28 with pilot-scale production >1.5 g L −1 29 .…”

Section: Introductionmentioning

confidence: 99%

“…PTM D1 ( 3 ) and PTM ML14 ( 5 ), dimeric analogues of PTM previously isolated, 18,20 are less prone to renal excretion and are converted into their active monomeric forms 1 and 4 , respectively, in vivo. Amide hydrolysis was seen as a major metabolite detected in in vitro microsome stability experiments and was observed in liver and kidney tissue after in vivo dosing of PTM, with minimal amounts seen in plasma.…”

Section: Introductionmentioning

confidence: 99%

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin

Dong

Rudolf

Lin

et al. 2017

Bioorganic & Medicinal Chemistry

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Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea- and carbamate-PTM analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities.

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“…Although none of the isolated PTM analogues showed antibacterial activity up to 80 μg per disk, with PTM, at 5 μg per disk, as a positive control, these findings provided additional experimental data supporting the current structure-activity relationship (SAR) for PTM. 10,14 …”

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A Mutasynthetic Library of Platensimycin and Platencin Analogues

2016

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Inactivation of ptmB1, ptmB2, ptmT2, or ptmC in Streptomyces platensis SB12029, a platensimycin (PTM) and platen-cin (PTN) overproducer, revealed that PTM and PTN biosynthesis features two distinct moieties that are individually constructed and convergently coupled to afford PTM and PTN. A focused library of PTM and PTN analogues was generated by mutasynthesis in the ΔptmB1 mutant S. platensis SB12032. Of the 34 aryl variants tested, 18 were incorporated with high titers.

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Antibacterial sulfur-containing platensimycin and platencin congeners from Streptomyces platensis SB12029

Cited by 25 publications

References 26 publications

Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin

A Mutasynthetic Library of Platensimycin and Platencin Analogues

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